Cyclohexapeptides having antimicrobial activity

ABSTRACT

This invention relates to new polypeptide compounds represented by general formula (I), wherein R 1 and R 2 are as defined in the description and pharmaceutically acceptable salt thereof which have antimicrobial activities (especially antifungal activities), inhibitory activity on &amp;bgr; -1,3-glucan synthase, to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the prophylactic and/or therapeutic treatment of infectious disease including Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia in a human being or an animal.

TECHNICAL FIELD

[0001] The present invention relates to new polypeptide compound and asalt thereof which are useful as a medicament.

BACKGROUND ART

[0002] In U.S. Pat. No. 5,376,634, there are disclosed the polypeptidecompound and a pharmaceutically acceptable salt thereof, which haveantimicrobial activities (especially antifungal activity).

DISCLOSURE OF INVENTION

[0003] The present invention relates to new polypeptide compound and asalt thereof.

[0004] More particularly, it relates to new polypeptide compound and asalt thereof, which have antimicrobial activities [especially,antifungal activities, in which the fungi may include Asperaillus,Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophvte,Malassezia, Fusarium and the like.], inhibitory activity on β-1,3-glucansynthase, and further which are expected to be useful for theprophylactic and/or therapeutic treatment of Pneumocystis cariniiinfection (e.g. Pneumocystis carinii pneumonia) in a human being or ananimal, to a process for preparation thereof, to a pharmaceuticalcomposition comprising the same, and to a method for the prophylacticand/or therapeutic treatment of infectious diseases includingPneumocystic carinii infection (e.g. Pneumocystis carinii pneumonia) ina human being or an animal.

[0005] The object polypeptide compound of the present invention are newand can be represented by the following general

[0006] wherein

[0007] R¹ is aroyl substituted with heterocyclic group which has asuitable substituent selected from the group consisting of aryl havingcyclo(lower)alkyloxy,

[0008] aryl having morpholinyl,

[0009] aryl having aryloxy(lower)alkoxy,

[0010] heterocyclic group having cyclo(lower)alkyl,

[0011] heterocyclic group having higher alkyl,

[0012] ar(lower)alkyl having lower alkoxy, and

[0013] cyclo(lower)alkyl which may have one or more suitablesubstituent(s);

[0014] aroyl substituted with heterocyclic group which has hydroxy andmay have additional one or more suitable substituent(s);

[0015] aroyl substituted with piperidyl which has aryl having loweralkoxy;

[0016] aroyl substituted with thiadiazolyl which has a suitablesubstituent selected from the group consisting

[0017] of aryl having pentyl,

[0018] aryl having hexyl,

[0019] aryl having methoxy,

[0020] aryl having butoxy, and

[0021] aryl having higher alkoxy;

[0022] aroyl substituted with aryl which has aryl having pentyloxy;

[0023] aroyl substituted with piperazinyl which has 3- hexyloxyphenyl;

[0024] aroyl substituted with 1,2,3,6-tetrahydropyridyl which may haveone or more suitable substituent(s);

[0025] aroyl substituted with thienyl which may have one or moresuitable substituent(s);

[0026] aroyl substituted with furyl which may have one or more suitablesubstituent(s);

[0027] aroyl substituted with heterocyclic(lower)alkyl which may haveone or more suitable substituent(s);

[0028] aroyl substituted with ar(lower)alkynyl which may have one ormore suitable substituent(s);

[0029] lower alkanoyl substituted with thiazolyl which may have one ormore suitable substituent(s); aroyl substituted with imidazothiadiazolylwhich may have one or more suitable substituent(s);

[0030] aroyl substituted with isoxazolyl having halogen which may haveone or more suitable substituent(s);

[0031] or

[0032] 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl;

[0033] and

[0034] R² is hydroxy, hydroxysulfonyloxy or lower alkoxy, with provisothat

[0035] R² is not hydroxysulfonyloxy, when R¹ is4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl.

[0036] The new polypeptide compound [I] and a salt thereof can beprepared by the process as illustrated in the following reaction scheme.

[0037] wherein R¹ and R² are as defined above,

[0038] R_(a) ² is hydroxysulfonyloxy,

[0039] R_(b) ² is hydroxy or

[0040] R_(c) ² is lower alkoxy.

[0041] The starting compound [IIb] and [TIc] or a salt thereof are noveland can be prepared by the following schemes.

[0042] Wherein Rd is lower alkoxy.

[0043] Suitable salts of the object polypeptide compound [I] arepharmaceutically acceptable, conventional non-toxic salts and mayinclude a salt with a base or an acid addition salt such as a salt withan inorganic base, for example, an alkali metal salt (e.g., sodium salt,potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt,magnesium salt, etc.), an ammonium salt;

[0044] a salt with an organic base, for example, an organic amine salt(e.g., triethylamine salt, pyridine salt, picoline salt, ethanolaminesalt, triethanolamine salt, dicyclohexylamine salt,N,NI-dibenzylethylenediamine salt, etc.);

[0045] an inorganic acid addition salt (e.g., hydrochloride,hydrobromide, sulfate, phosphate, etc.); an organic carboxylic sulfonicacid addition salt (e.g., formate, acetate, trifluoroacetate, maleate,tartrate, fumarate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g.,arginine, aspartic acid, glutamic acid, etc.).

[0046] In the above and subsequent descriptions of the presentspecification, suitable examples and illustration of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows

[0047] The term “lower” is used to intend a group having 1 to 6 carbonatom(s), unless otherwise provided.

[0048] The term “higher” is used to intend a group having 7 to 20 carbonatoms, unless otherwise provided.

[0049] Suitable example of “one or more” may be the number of 1 to 6, inwhich the preferred one may be the number of 1 to 3.

[0050] Suitable example of “lower alkanoyl” may include straight orbranched one such as formyl, acetyl, 2-methylacetyl, 2,2-dimethylacetyl,propionyl, butyryl, isobutyryl, pentanoyl, 2,2-dimethylpropionyl,hexanoyl, and the like.

[0051] Suitable example of “suitable substituent(s)” may include loweralkoxy as mentioned below, higher alkoxy as mentioned below, lower alkylas mentioned below, higher alkyl as mentioned below, higheralkoxy(lower)alkyl, lower alkoxycarbonyl, oxo, aryl which may have oneor more lower alkoxy, aryl which may have one or more higher alkoxy,aryl which may have one or more lower alkyl, aryl which may have one ormore higher alkyl, aryl substituted with aryl which may have one or morelower alkoxy, aryl substituted with aryl which may have one or morehigher alkoxy, aryl substituted with aryl which may have one or morelower alkyl, aryl substituted with aryl which may have one or morehigher alkyl, aroyl which may have one or more lower alkoxy, aroyl whichmay have one or more higher alkoxy, aroyl which may have one or morelower alkyl, aroyl which may have one or more higher alkyl, heterocyclicgroup which may have one or more lower alkoxy, heterocyclic group whichmay have one or more higher alkoxy, aryl havingheterocyclic(higher)alkoxy, heterocyclic group which may have arylhaving higher alkoxy, heterocyclic group which may have aryl havinglower alkoxy(higher)alkoxy, heterocyclic group which may have arylhaving lower alkoxy, lower alkoxy(lower)alkyl, halo(lower)alkoxy, loweralkenyloxy, halo(higher)alkoxy, lower alkoxy(higher)alkoxy, aryl whichmay have one or more lower alkoxy(lower)alkoxy, heterocyclic group, arylwhich may have one or more lower alkoxy(higher)alkoxy, aryl which mayhave one or more higher alkenyloxy, cyclo(lower)alkyl which may havearyl, aryl substituted with heterocyclic group which may have loweralkyl and oxo, cyclo(lower)alkyl which may have one or more lower alkyl,aryl which may have cyclo(lower)alkyl, aryl which may have heterocyclicgroup, and the like.

[0052] Suitable example of “lower alkoxy” may include straight orbranched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neo-pentyloxy,hexyloxy, isohexyloxy, and the like, in which the preferred one may bemethoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isohexyloxy.

[0053] Suitable example of “higher alkoxy” may include straight orbranched one such as heptyloxy, octyloxy, 3,5-dimethyloctyloxy,3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy,tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy,nonadecyloxy, icosyloxy, and the like,

[0054] in which the preferred one may be (C₇-C₁₄)alkoxy, and the morepreferred one may be heptyloxy and octyloxy.

[0055] Suitable example of “lower alkyl” may include straight orbranched one having 1 to 6 carbon atom(s), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl,tert-pentyl, neo-pentyl, hexyl, isohexyl, and the like,

[0056] in which the preferred one may be methyl, pentyl, hexyl andisohexyl.

[0057] Suitable example of “higher alkyl” may include straight orbranched one having 7 to 20 carbon atoms, such as heptyl, octyl,3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl,nonadecyl, icosyl, and the like,

[0058] in which the preferred one may be (C₇-Cl₄)alkyl, and the morepreferred one may be heptyl, octyl, nonyl and decyl.

[0059] Suitable example of “aryl” and “ar” moiety may include phenylwhich may have lower alkyl (e.g., phenyl, mesityl, tolyl, etc.),naphthyl, anthryl, and the like, in which the preferred one may bephenyl and naphthyl.

[0060] Suitable example of “aroyl” may include benzoyl, toluoyl,naphthoyl, anthrylcarbonyl, and the like, in which the preferred one maybe benzoyl and naphthoyl.

[0061] Suitable example of “heterocyclic group” and “heterocyclic”moiety may include unsaturated 3 to 8-membered (more preferably 5 or6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s),for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl (e.g., 4H-1,2,4- triazolyl, lH-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.;

[0062] saturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

[0063] unsaturated condensed heterocyclic group containing 1 to 4nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.),etc.;

[0064] saturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

[0065] unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

[0066] unsaturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

[0067] saturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

[0068] unsaturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

[0069] unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, imidazothiadiazolyl, etc.;

[0070] unsaturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

[0071] saturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing an oxygen atom, for example,tetrahydrofuran, tetrahydropyran, etc.;

[0072] unsaturated 3 to 8-membered (more preferably 5 or 6- membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

[0073] unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

[0074] unsaturated condensed heterocyclic group containing an oxygenatom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; andthe like.

[0075] Suitable example of “halo” may include fluoro, chloro, bromo andiodo.

[0076] Suitable example of “lower alkenyloxy” may include vinyloxy,1-(or 2-)propenyloxy, 1-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or4-)pentenyloxy, 1-(or 2- or 3- or 4- or 5-)hexenyloxy, and the like, inwhich the preferred one may be (C₂-C₆)alkenyloxy, and the most preferredone may be 5-hexenyloxy.

[0077] Suitable example of “higher alkenyloxy” may include(C₇-C₂₀)alkenyloxy, in which the preferred one may be 6- heptenyloxy and7-octenyloxy.

[0078] Suitable example of “cyclo(lower)alkyl” may include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which thepreferred one may be cyclo(C₄-C₆)alkyl, and the most preferred one maybe cyclohexyl.

[0079] Suitable example of “ar(lower)alkyl” may include benzyl,phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,naphthylpentyl, naphthylhexyl, and the like, in which the preferred onemay be phenyl(C₁-C₄)alkyl, and the most preferred one may be phenethyl.

[0080] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with heterocyclic group which has a suitable substituentselected from the group consisting of aryl having cyclo(lower)alkyloxy,aryl having morpholinyl, aryl having aryloxy(lower)alkoxy, heterocyclicgroup having cyclo(lower)alkyl, heterocyclic group having higher alkyl,ar(lower)alkyl having lower alkoxy and cyclo(lower)alkyl which may haveone or more suitable substituent(s)” can be referred to aforementioned“aroyl”, in which the preferred one may be benzoyl.

[0081] Suitable example of said “heterocyclic group” moiety can bereferred to aforementioned “heterocyclic group”, in which the preferredone may be “saturated 3 to 8-membered heteromonocyclic group containing1 to 4 nitrogen atom(s)” and “unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s)” , and the most preferred one may be piperidyl,piperazinyl and thiadiazolyl.

[0082] Suitable example of “aryl having cyclo(lower)alkyloxy” moiety maybe cyclopropyloxyphenyl, cyclobutyloxyphenyl, cyclopentyloxyphenyl,cyclohexyloxyphenyl, cyclopentyloxynaphthyl, cyclohexyloxynaphthyl,cyclohexyloxyanthryl, and the like, in which the preferred one may bephenyl having cyclo(C₄-C₆)alkyloxy, and the most preferred one may becyclohexyloxyphenyl.

[0083] Suitable example of “aryl having morpholinyl” moiety may be4-morpholinylphenyl, 3-morpholinylnaphthyl, 2-morpholinylanthryl, andthe like, in which the preferred one may be morpholinylphenyl and themost preferred one may be morpholinophenyl.

[0084] Suitable example of “aryl having aryloxy(lower)alkoxy” moiety maybe phenoxymethoxyphenyl, phenoxyethoxyphenyl, phenoxypropoxyphenyl,phenoxybutoxyphenyl, phenoxypentyloxynaphthyl, phenoxyhexyloxyphenyl,naphthyloxymethoxyphenyl, naphthyloxyethoxynaphthyl,naphthyloxypropoxyphenyl, anthryloxybutoxynaphthyl, and the like, inwhich the preferred one may be phenoxy(C₁-C)- alkoxyphenyl, and the mostpreferred one may be phenoxypropoxyphenyl.

[0085] Suitable example of “theterocyclic group havingcyclo(lower)alkyl” moiety may be saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) havingcyclopropyl, saturated 3 to 8-membered heteromonocyclic group containing1 to 4 nitrogen atom(s) having cyclobutyl, saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) havingcyclopentyl, saturated 3 to 8-membered heteromonocyclic group containing1 to 4 nitrogen atom(s) having cyclohexyl, and the like, in which thepreferred one may be piperidyl having cyclo(C₄- C₆)alkyl, and the mostpreferred one may be piperidyl having cyclohexyl.

[0086] Suitable example of “heterocyclic group having higher alkyl”moiety may be saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) having heptyl, saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)having octyl, saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) having nonyl, saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)having decyl, saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) having undecyl, saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)having dodecyl, saturated 3 to 8- membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) having tridecyl, saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)having tetradecyl, and the like, in which the preferred one may bepiperidyl having (C₇-C₁₄)alkyl, and the most preferred one may bepiperidyl having octyl.

[0087] Suitable example of “ar(lower)alkyl having lower alkoxy” moietymay be methoxybenzyl, ethoxybenzyl, propoxybenzyl, butoxybenzyl,pentyloxybenzyl, pentyloxyphenethyl, hexyloxyphenethyl,pentyloxyphenylpropyl, hexyloxyphenylbutyl, pentyloxyphenylpentyl,hexyloxyphenylhexyl, and the like, in which the preferred one may bephenethyl having (C₄-C₆)alkoxy, and the most preferred one may behexyloxyphenethyl.

[0088] Suitable example of “suitable substituent(s)” moiety in the termof “cyclo(lower)alkyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned suitablesubstituent(s)”, in which the preferred one may be cyclo(lower)alkyl,and the more preferred one may be cyclo(C₄-C₆)alkyl, and the mostpreferred one may be cyclohexyl.

[0089] Suitable example of “cyclo(lower)alkyl which may have one or moresuitable substituent(s)” may be cyclo(lower)alkyl which may havecyclo(lower)alkyl or lower alkyl, in which the preferred one may becyclo(C₄-C₆)alkyl having cyclo(C₄-C₆)- alkyl or (C₄-C₆)alkyl, and themost preferred one may be cyclohexyl having cyclohexyl or cyclohexylhaving pentyl.

[0090] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with heterocyclic group which has hydroxy and may haveadditional one or more suitable substituent(s)” can be referred toaforementioned “aroyl”, in which the preferred one may be benzoyl.

[0091] Suitable example of “heterocyclic group ” moiety in the term of“aroyl substituted with heterocyclic group which has hydroxy and mayhave additional one or more suitable substituent(s)” can be referred toaforementioned “heterocyclic group”, in which the preferred one may besaturated 3 to 8-membered heterocyclic group containing 1 to 4 nitrogenatom(s), and the most preferred one may be piperidyl.

[0092] Suitable example of “suitable substituent(s)” moiety in saidgroup may be aryl having lower alkoxy such as methoxyphenyl,ethoxyphenyl, propoxyphenyl, butoxyphenyl, pentyloxyphenyl,hexyloxyphenyl, pentyloxynaphthyl, hexyloxynaphthyl, hexyloxyanthryl,and the like, in which the preferred one may be phenyl having(C₄-C₆)alkoxy, and the most preferred one may be hexyloxyphenyl.

[0093] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with piperidyl which has aryl having lower alkoxy” can bereferred to aforementioned “aroyl”, in which the preferred one may bebenzoyl.

[0094] Suitable example of “aryl” moiety in the term of “aroylsubstituted with piperidyl which has aryl having lower alkoxy” can bereferred to aforementioned “aryl”, in which the preferred one may bephenyl.

[0095] Suitable example of “aroyl substituted with piperidyl which hasaryl having lower alkoxy” may be benzoyl substituted with piperidylwhich has hexyloxyphenyl, naphthoyl substituted with piperidyl which hashexyloxynaphthyl, and the like, in which the preferred one may bebenzoyl substituted with piperidyl which has phenyl having(C₄-C₆)alkoxy, and the most preferred one may be benzoyl substitutedwith piperidyl which has hexyloxyphenyl.

[0096] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with thiadiazolyl which has a suitable substituent selectedfrom the group consisting of aryl having pentyl, aryl having hexyl, arylhaving methoxy, aryl having butoxy and aryl having higher alkoxy” can bereferred to aforementioned “aroyl”, in which the preferred one may bebenzoyl.

[0097] Suitable example of “aryl” moiety in the term of “aryl havingpentyl, aryl having hexyl, aryl having methoxy, aryl having butoxy andaryl having higher alkoxy” can be referred to aforementioned “aryl”, inwhich the preferred one may be phenyl.

[0098] Suitable example of “aroyl substituted with thiadiazolyl whichhas a suitable substituent selected from the group consisting of arylhaving pentyl, aryl having hexyl, aryl having methoxy, aryl havingbutoxy and aryl having higher aloxy” may be benzoyl substituted withthiadiazolyl which has a suitable substituent selected from the groupconsisting of pentylphenyl, hexylphenyl, methoxyphenyl, butoxyphenyl andheptyloxyphenyl.

[0099] Suitable example of Yaroylfl moiety in the term of “aroylsubstituted with aryl which has aryl having pentyloxyll can be referredto aforementioned “aroyl¹¹ ₁ in which the preferred one may be benzoyl.

[0100] Suitable example of “aryl” moiety in the term of “aroylsubstituted with aryl which has aryl having pentyloxy” can be referredto aforementioned “aryl”, in which the preferred one may e phenyl.

[0101] Suitable example of “aroyl substitu ted with aryl which has arylhaving pentyloxyll may be benzoyl substituted with phenyl which haspentyloxyphenyl, naphthoyl substituted with naphthyl which haspentyloxyphenyl, anthrylcarbonyl substituted with phenyl which haspentyloxynaphthyl, and the like, in which the preferred one may bebenzoyl substituted with phenyl which has pentyloxyphenyl.

[0102] Suitable example of “aroyl” in the term of “aroyl substitutedwith piperazinyl which has 3-hexyloxyphenyl” can be referred toaforementioned “aroyl”, in which the preferred one may be benzoyl.

[0103] Suitable example of “aroyl substituted with piperazinyl which has3-hexyloxyphenyl” may be benzoyl substituted with piperazinyl which has3-hexyloxyphenyl.

[0104] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with 1,2,3,6-tetrahydropyridyl which may have one or moresuitable substituent(s)” can be referred to aforementioned “aroyl” inwhich the preferred one may be benzoyl.

[0105] Suitable example of “suitable substituent(s)” moiety in the termof “aroyl substituted with 1,2,3,6-tetrahydropyridyl which may have oneor more suitable substituent(s)” can be referred to aforementioned“suitable substituent(s)”, in which the preferred one may be aryl whichmay have one or more lower alkoxy, and the more preferred one may bephenyl which may have a (C₄-C₆)alkoxy, and the most preferred one may behexyloxyphenyl.

[0106] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with thienyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “aroyl”, in which thepreferred one may be benzoyl.

[0107] Suitable example of “suitable substituent(s)” in the term of“aroyl substituted with thienyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “suitablesubstituent(s)”, in which the preferred one may be aryl which may haveone or more lower alkoxy, and the more preferred one may be phenyl whichmay have a (C₄-C₆)alkoxy, and the most preferred one may bepentyloxyphenyl.

[0108] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with furyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “aroyl”, in which thepreferred one may be benzoyl.

[0109] Suitable example of “suitable substituent(s)” moiety in the termof “aroyl substituted with furyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “suitablesubstituent(s)”, in which the preferred one may be aryl which may haveone or more lower alkoxy, and the more preferred one may be phenyl whichmay have a (C₄-C₆)alkoxy, and the most preferred one may bepentyloxyphenyl.

[0110] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with heterocyclic(lower)alkyl which may have one or moresuitable substituent(s)” can be referred to aforementioned “aroyl”, inwhich the preferred one may be benzoyl.

[0111] Suitable example of “heterocyclic” moiety in the term of aroylsubstituted with heterocyclic(lower)alkyl which may have one or moresuitable substituent(s)” can be referred to aforementioned“heterocyclic” moiety, in which the preferred one may be saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),and the most preferred one may be piperazinyl.

[0112] Suitable example of “suitable substituent(s)” moiety in the termof “aroyl substituted with heterocyclic(lower)alkyl which may have oneor more suitable substituent(s)” can be referred to aforementioned“suitable substituent(s)”, in which the preferred one may be aryl whichmay have cyclo(lower)alkyl, and the more preferred one may be phenylwhich has cyclo(C₄-C₆)alkyl, and the most preferred one may becyclohexylphenyl.

[0113] Suitable example of “aroyl substituted withheterocyclic(lower)alkyl which may have one or more suitablesubstituent(s)” may be benzoyl substituted with heterocyclic(C₁-C₆)alkylwhich may have phenyl which may have cyclo(C₃-C₆)alkyl, in which thepreferred one may be benzoyl substituted with (C₁-C₄)alkyl havingsaturated 3 to 8- membered heteromonocyclic group containing 1 to 4nitrogen atom(s) which may have phenyl which has cyclo(C₄-C₆)alkyl, andthe most preferred one may be benzoyl substituted with piperazinylmethylwhich has phenyl having cyclohexyl or benzoyl substituted withpiperazinylethyl which has phenyl having cyclohexyl.

[0114] Suitable example of “aroyl¹¹ moiety in the term of “aroylsubstituted with ar(lower)alkynyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned aroyl”, in which thepreferred one may be benzoyl.

[0115] Suitable example of “ar(lower)alkynyl” moiety in the term of“aroyl substituted with ar(lower)alkynyl which may have one or moresuitable substituent(s)” may be phenylethynyl, phenylpropynyl,phenylbutynyl, naphthylpentynyl, phenylhexynyl, naphthylethynyl,anthrylpropynyl, and the like, in which the preferred one may bephenyl(C₂-C₄)alkynyl, and the most preferred one may be phenylethynyl.

[0116] Suitable example of “¹suitable substituent(s)” moiety in the termof “aroyl substituted with ar(lower)alkynyl which may have one or moresuitable substituent(s)” can be referred to aforementioned “suitablesubstituent(s)”, in which the preferred one may be lower alkoxy, and themore preferred one may be (C₄-C₆)alkoxy, and the most preferred one maybe pentyloxy.

[0117] Suitable example of “aroyl substituted with ar(lower)alkynylwhich may have one or more suitable substituent(s)” may be benzoylsubstituted with phenyl(lower)alkynyl which may have lower alkoxy, inwhich the preferred one may be benzoyl substituted with phenyl-(C₂-C₄)alkynyl which has (C₄-C₆)alkoxy, and the most preferred one maybe benzoyl substituted with phenylethynyl which has pentyloxy.

[0118] Suitable example of “lower alkanoyl” moiety in the term of “loweralkanoyl substituted with thiazolyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “lower alkanoyl”, inwhich the preferred one may be (C₁-C₄)alkanoyl, and the most preferredone may be formyl.

[0119] Suitable example of “suitable substituent(s)” in the term of“lower alkanoyl substituted with thiazolyl which may have one or moresuitable substituent(s)” can be referred to aforementioned “suitablesubstituent(s)”, in which the preferred one may be aryl substituted witharyl having lower alkoxy, and the more preferred one may be phenylsubstituted with phenyl having (C₄-C₆)alkoxy, and the most preferred onemay be phenyl substituted with pentyloxyphenyl.

[0120] Suitable example of “aroyl” moiety in the term of “aroylsubstituted with imidazothiadiazolyl which may have one or more suitablesubstituent(s)” can be referred to aforementioned “aroyl”, in which thepreferred one may be benzoyl.

[0121] Suitable example of “suitable substituent(s)” moiety in the termof “aroyl substituted with imidazothiadiazolyl which may have one ormore suitable substituent(s)” can be referred to aforementioned“suitable substituent(s)”, in which the preferred one may be aryl whichmay have one or more lower alkoxy or aryl substituted with aryl, and themore preferred one may be aryl having (C₂-C₆)alkoxy or aryl havingphenyl, and the most preferred one may be phenyl having pentyloxy,phenyl having ethoxy or phenyl having phenyl.

[0122] Suitable example of “aroyl substituted with imidazothiadiazolylwhich may have one or more suitable substituent(s)!v may be benzoylsubstituted with imidazothiadiazolyl which has phenyl having(C₂-C₆)alkoxy or benzoyl substituted with imidazothiadiazolyl which hasaryl having phenyl, and the most preferred one may be benzoylsubstituted with imidazothiadiazolyl which has phenyl having pentyloxy,benzoyl substituted with imidazothiadiazolyl which has phenyl havingethoxy or benzoyl substituted with imidazothiadiazolyl which has phenylhaving phenyl.

[0123] Suitable example of !aroylfl moiety in the term of “aroylsubstituted with isoxazolyl having halogen which may have one or moresuitable substituent(s)” can be referred to aforementioned l“aroyl”, inwhich the preferred one may be benzoyl.

[0124] Suitable example of ¹¹suitable substituent(s)” moiety in the termof “aroyl substituted with isoxazolyl having halogen which may have oneor more suitable substituent(s)” can be referred to aforementioned“suitable substituent(s)¹¹ ₁ in which the preferred one may be arylwhich may have lower alkoxy, the preferred one may be phenyl which has(C₄-C₆)- alkoxy, and the most preferred one may be phenyl havingpentyloxy.

[0125] Suitable example of “aroyl substituted with isoxazolyl havinghalogen which may have one or more suitable substituent(s)” may bebenzoyl substituted with isoxazolyl having chloro which has phenylhaving (C₄-C₆)alkoxy, and the most preferred one may be benzoylsubstituted with isoxazolyl having chloro which has phenyl havingpentyloxy.

[0126] The processes for preparing the object polypeptide compound [I]and the starting compounds [IIb] and [IIc] or a salt thereof of thepresent invention are explained in detail in the following.

Process 1

[0127] The object polypeptide compound [I] or a salt thereof can beprepared by reacting the compound [II] or its reactive derivative at theamino group or a salt thereof with the compound [III] or its reactivederivative at the carboxy group or a salt thereof.

[0128] Suitable reactive derivative at the carboxy group of the compound[III] may include an acid halide, an acid anhydride, an activated amide,an activated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g., methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g., acetic acid, propionic acid, butyric acid,isobutyric acid, pivaric acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.]; or aromatic carboxylicacid [e.g., benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole, tetrazole or 1-hydroxy-lH- benzotriazole; oran activated ester [e.g., cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂N=CH-] ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachloropentyl ester, mesylphenyl ester, phenylazophenyl ester,phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-lH- benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the mind of the compound [III] to beused.

[0129] Suitable salts of the compound [III] and its reactive derivativecan be referred to the ones as exemplified for the object polypeptidecompound [I].

[0130] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g., methanol, ethanol, etc.], acetone,dioxane, acetonitrile, chloroform, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,pyridine or any other organic solvent which does not adversely influencethe reaction. These conventional solvent may also be used in a mixturewith water.

[0131] In this reaction, when the compound [III] is used in a free acidform or its salt form, the reaction is preferably carried out in thepresence of a conventional condensing agent such asN,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,NT-diethylcarbodiimide; N,NI-diisopropylcarbodiimide;N-ethyl-N-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkylhaloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.];triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH- benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorousoxychloride, methanesulfonyl chloride, etc.; or the like.

[0132] The reaction may also be carried out in the presence of aninorganic or organic base such as an alkali metal carbonate, alkalimetal bicarbonate, tri(lower)alkylamine, pyridine,di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.),N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

[0133] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0134] The starting compound [IIa] is a known compound. It can beprepared by fermentation and synthetic processes disclosed in EP 0462531A2.

[0135] A culture of Coleophoma sp. F-11899, which is used in saidfermentation process, has been deposited with National Institute ofBioscience and Human-Technology Agency of Industrial Science andTechnology (former name Fermentation Research Institute Agency ofIndustrial Science and Technology) (1-3, Higashi 1-chome, Tsukuba-shi,IBARAKI 305, JAPAN) on October 26, 1989 under the number of FERMBP-2635.

Process 2

[0136] The compound [Ib] or a salt thereof can be prepared by subjectingthe compound [Ia] or its reactive derivative at the sulfonic acid groupor a salt thereof to hydrolysis reaction of the sulfonic acid group.

[0137] The hydrolysis is preferably carried out in the presence of abase or an acid including Lewis acid.

[0138] Suitable base may include an inorganic base and an organic basesuch as an alkali metal [e.g., sodium, potassium, etc.], an alkalineearth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonateor hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine,triethylamine, etc.], picoline, 1,5- diazabicyclo[4.3.0]-non-5-ene, orthe like.

[0139] Suitable acid may include an organic acid [e.g., formic acid,acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid,etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen, chloride, hydrogen bromide, etc.].

[0140] The elimination using Lewis acid such as trihaloacetic acid[e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like ispreferably carried out in the presence of cation trapping agents [e.g.,anisole, phenol, etc.].

[0141] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol,etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N- dimethylformamide, N,N-dimethylacetamide orany other organic solvent which do not adversely affect the reaction, orthe mixture thereof.

[0142] The reaction temperature is not critical and the reaction isusually carried out under cooling to warming.

Process 3

[0143] The compound [Ic] or a salt thereof can be prepared by subjectingthe compound [Ib] or its reactive derivative at the hydroxy group or asalt thereof with the diazo compound [e.g., diazomethane,phenyldiazomethane, diphenyldiazomethane, ~-diazopropionic acid, etc.]or a salt thereof to alkylation reaction of the hydroxy group.

[0144] This reaction is usually carried out in the solvent such aswater, alcohol [e.g., methanol, ethanol, etc.], benzene,N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride,ethylene dichloride, chloroform, dioxane, diethyl ether, acetonitrile orany other solvents which do not adversely affect the reaction, or themixture thereof.

[0145] The reaction temperature is not critical and the reaction isusually carried out under cooling to heating.

[0146] The reaction may be usually carried out in the presence of anacid including Lewis acid.

[0147] Suitable acid may include an organic acid [e.g. formic acid,acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid,etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g.,zinc chloride, zinc bromide, etc.), etc.] and the like.

[0148] The reaction may be also carried out in the presence of aninorganic or an organic base such as an alkali metal [e.g., sodium,potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide,potassium, hydroxide, etc.], an alkali metal hydrogencarbonate [e.g.,sodium lhydrogencarbonate, potassium hydrogencarbonate, etc.], alkalimetal carbonate [e.g., sodium carbonate, potassium carbonate, etc.],tri(lower)alkylamine [e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.], alkali metal hydride [e.g., sodiumhydride, etc.], alkali metal (lower)alkoxide [e.g. sodium methoxide,sodium ethoxide, etc.], pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

[0149] When the base, the acid and/or the starting compound are inliquid, they can be used also as a solvent.

Process A

[0150] The starting compound [IIb] or a salt thereof can be prepared bysubjecting the compound [IIa] or its reactive derivative at the sulfonicacid group or a salt thereof to hydrolysis reaction of the sulfonic acidgroup.

[0151] This reaction can be carried out in a similar manner to that ofProcess 2 mentioned in the above, and therefore the reaction mode andreaction conditions [e.g., base, acid, catalyst, solvent, reactiontemperature, etc.] of this reaction are to be referred to those asexplained in Process 2.

Process B

[0152] The starting compound [IIc] or a salt thereof can be prepared bysubjecting the compound [IIb] or its reactive derivative at the hydroxygroup or a salt thereof with the diazo compound [e.g., diazomethane,phenyldiazomethane, diphenyldiazomethane, β-diazopropionic acid, etc.]or a salt thereof to alkylation reaction of the hydroxy group.

[0153] This reaction can be carried out in a similar manner to that ofProcess 3 mentioned in the above, and therefore the reaction mode andreaction conditions [e.g., base, acid, catalyst, solvent, reactiontemperature, etc.] of this reaction are to be referred to those asexplained in Process 3.

[0154] The compounds obtained by the above Processes 1 to 3 andProcesses A and B can be isolated and purified by a conventional methodsuch as pulverization, recrystallization, 2c column-chromatography,high-performance liquid chromatography (HPLC), reprecipitation, or thelike.

[0155] The compounds obtained by the above Processes 1 to 3 andProcesses A and B may be obtained as its hydrate, and its hydrate isincluded within the scope of this invention.

[0156] It is to be noted that each of the object compound [I] mayinclude one or more stereoisomer such as optical isomer(s) andgeometrical isomer(s) due to asymmetric carbon atom(s) and doublebond(s) and all such isomers and mixture thereof are included within thescope of this invention.

[0157] Biological property of the polypeptide compound [Il of thepresent invention In order to show the usefulness of the polypeptidecompound [I] of the present invention, the biological data of therepresentative compound is explained in the following.

Test (Antimicrobial activity)

[0158] In vitro antimicrobial activity of the compound of Example 15disclosed later was determined by the two-fold agar-plate dilutionmethod as described below.

Test Method

[0159] One loopful of an overnight culture of each test microorganism inSabouraud broth containing 2% Glucose (105 viable cells per ml) wasstreaked on yeast nitrogen base dextrose agar (YNBDA) containing gradedconcentrations of the object polypeptide compound [I], and the minimalinhibitory concentration (MIC) was expressed in terms of [g/ml afterincubation at 30° C for 24 hours.

Test Result

[0160] MIC (μg/ml) Test compound The object compound Test organism ofExample 15 candida albicans FP-633 0.1

[0161] From the test result, it is realized that the object polypeptidecompound [I] of the present invention has an antimicrobial activity(especially, antifungal activity).

[0162] The pharmaceutical composition of the present invention can beused in the form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains the object polypeptide compound[I] or a pharmaceutically acceptable salt thereof, as an activeingredient in admixture with an organic or inorganic carrier orexcipient which is suitable for rectal; pulmonary (nasal or buccalinhalation); ocular; external (topical); oral administration; parenteral(including subcutaneous, intravenous and intramuscular) administrations;insufflation (including aerosols from metered dose inhalator);nebulizer; or dry powder inhalator.

[0163] The active ingredient may be compounded, for example, with theusual non-toxic, pharmaceutically acceptable carriers in a solid formsuch as granules, tablets, dragees, pellets, troches, capsules, orsuppositories; creams; ointments; aerosols; powders for insufflation; ina liquid form such as solutions, emulsions, or suspensions forinjection; ingestion; eye drops; and any other form suitable for use.And, if necessary, there may be included in the above preparationauxiliary substance such as stabilizing, thickening, wetting,emulsifying and coloring agents; perfumes or buffer; or any othercommonly may be used as additives.

[0164] The object polypeptide compound [I] or a pharmaceuticallyacceptable salt thereof is/are included in the pharmaceuticalcomposition in an amount sufficient to produce the desired antimicrobialeffect upon the process or condition of diseases.

[0165] For applying the composition to human, it is preferable to applyit by intravenous, intramuscular, pulmonary, oral administration, orinsufflation. While the dosage of therapeutically effective amount ofthe object polypeptide compound [I] varies form and also depends uponthe age and condition of each individual patient to be treated, in thecase of intravenous administration, a daily dose of 0.01-20 mg of theobject polypeptide compound [I] per kg weight of human being in the caseof intramuscular administration, a daily dose of 0.1-20 mg of the objectpolypeptide compound [I] per kg weight of human being, in case of oraladministration, a daily dose of 0.5-50 mg of the object polypeptidecompound [I] per kg weight of human being is generally given fortreating or preventing infectious diseases.

[0166] Especially in case of the treatment of prevention of Pneumocystiscarinii infection, the followings are to be noted.

[0167] For administration by inhalation, the compounds of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized as powders which may be formulated and thepowder compositions may be inhaled with the aid of an insufflationpowder inhaler device. The preferred delivery system for inhalation is ametered dose inhalation aerosol, which may be formulated as a suspensionor solution of compound in suitable propellants such as fluorocarbons orhydrocarbons.

[0168] Because of desirability to directly treat lung and bronchi,aerosol administration is a preferred method of administration.Insufflation is also a desirable method, especially where infection mayhave spread to ears and other body cavities.

[0169] Alternatively, parenteral administration may be employed usingdrip intravenous administration.

[0170] The following Preparations and Examples are given for the purposeof illustrating the present invention in more detail.

Preparation 1

[0171] To a suspension of sodium hydride (60% suspension in mineral oil)(1.18 g) in dimethylformamide (25 ml) was added1-acetyl-4-(4-hydroxyphenyl)piperazine (5 g) and bromocyclohexane (5.59ml) and stirred for 1 hour at 100° C. The reaction mixture was added toa mixture of water and ethyl acetate. The organic layer was taken anddried over magnesium sulfate. The magnesium sulfate was filtered off,and the filtrate was evaporated under reduced pressure to give1-acetyl-4-(4-cyclohexyloxyphenyl)piperazine (0.92 g).

Preparation 2

[0172] A solution of 3-[2-(4-morpholinophenylamino)ethyl]-2-oxazolidone(5 g) in 30% hydrobromic acid in acetic acid (35 ml) was stirred for 24hours at ambient temperature. The reaction mixture was pulverized withdiisopropyl ether. The precipitate was collected by filtration and addedto ethanol (35 ml). The solution was refluxed for 8 hours and pulverizedwith diisopropyl ether. The precipitate was collected by filtration togive 1-(4-morpholinophenyl)-piperazine dihydrobromide (7.42 g).

[0173] IR (KBr) : 1608.3, 1521.6, 1259.3, 889.0 cm l NMR (D₂0, 5)3.3-3.8 (12H, m), 4.1-4.2 (4H, m), 7.24 (2H, d, J=9.3Hz), 7.58 (2H, d,J=9.3Hz) APCI-MASS : m/z =248 (M+H)+

Preparation 3

[0174] To a solution of 1-tert-butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (6.856 g) in dichloromethane (34 ml) was addedtrifluoroacetic acid (17 ml) and stirred for 30 minutes at 40C. Thereaction mixture was adjusted to pH 12 with 2M aqueous NaOH. The organiclayer was separated, washed with water and dried over magnesium sulfateand evaporated under reduced pressure to give4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropiridine (3.59 g)

[0175] IR (KBr) 3263.0, 1604.5, 1511.9, 1251.6, 842.7 cm 1 NMR (CDC1₃₁o) : 0.90 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.6-1.9 (3H, m), 2.3-2.5(2H, m), 3.10 (2H, t, J=5.7Hz), 3.4-3.6 (2H, m), 3.95 (2H, t, J=6.5Hz),6.0-6.1 (1H, m), 6.85 (2H, d, J=8.9Hz), 7.30 (2H, d, J=8.9Hz) APCI-MASSm/z =260 (M+H)+

Preparation 4

[0176] A solution of 4-[4-(3-hydroxyphenyl)piperazin-1- yl]benzoic aciddihydrobromide (2.396 g) in a mixture of 5% NaOH aq. (16.7 ml) anddimethylsulfoxide (33.3 ml) was stirred for 30 minutes at 80° C. Then,1-bromohexane (0.88 ml) was added thereto and stirred for 8 hours at 80°C. The reaction mixture was added to water and adjusted to pH 2.0 withIN HCl. The produced precipitate was collected by filtration and driedunder reduced pressure to give 4-4-(3-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (3.74 g).

[0177] IR (KBr) : 1670.1, 1602.6, 1236.1, 1189.9 cm-¹ NMR (DMSO-d₆₁ o) :0.88 (3H t, J=6.9Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.2-3.5 (8H, m),3.93 (2H, t, J=6.4Hz), 6.38 (1H, d, J=8.OHz), 6.49 (1H, s), 6.55 (1H, d,J=8.OHz), 7.02 (2H, d, J=9.OHz), 7.12 (1H, dd, J=8.OHz), 7.79 (2H, d,J=9.OHz)

[0178] APCI-MASS : m/z =383 (M+H)+

Preparation 5

[0179] To a solution of methyl4-[5-[N-(tert-butoxycarbonyl)-piperidin-4-yl]-1,3,4-thiadiazol-2-yl]benzoate(1.28 g) in dichloromethane (12 ml) was added trifluoroacetic acid (25ml) at 0° C and the reaction mixture was stirred for 1 hour at roomtemperature . The solvents were removed under reduced pressure. Theprecipitate was triturated with diisopropyl ether, collected byfiltration, washed with diisopropyl ether and dried under reducedpressure to give 4-[5-(4-methoxycarbonylphenyl)-1,3,4-thiadiazol-2-yl]piperidinium trifluoroacetate (1.31 g).

[0180] IR (KBr) : 2956, 2840, 1722, 1673, 1436, 1282, 1211, 1180, 1124cm-1 NMR (DMSO-d₆, 5) : 2.0-2.2 (2H, m), 2.30 (2H, d, J=12.OHz), 3.0-3.2(2H, m), 3.4-3.7 (3H, m), 3.90 (3H, s), 8.12 (4H, s), 8.6-9.0 (2H, br)APCI-MASS m/z =304 (M+H)+free

Preparation 6

[0181] To a suspension of ethyl 4-bromobenzoate (1.37 g),(4-n-pentyloxyphenyl)acetylene (565 mg), triphenylphosphine (16 mg) andcopper(I) iodide (6 mg) in triethylamine (10 ml) and pyridine (4 ml) wasadded palladium(II) chloride bis(triphenylphosphine) (21 mg) and thereaction mixture was stirred for 24 hours at 80° C . After cooling, theprecipitate was filtered off, and the filtrate was evaporated underreduced pressure. The residue was taken up to dichloromethane, and thesolution was washed successively with 1N HCl, water, brine and driedover magnesium sulfate. The solvents were removed under reduced pressureand the residue was triturated with acetonitrile, collected byfiltration and dried under reduced pressure to give ethyl4-(4-n-pentyloxyphenylethynyl)benzoate (355 mg).

[0182] IR (KBr) : 2940, 2869, 1706, 1515, 1274, 1103 cm-¹ NMR (CDC1₃, 5): 0.93 (3H, t, J=7.OHz), 1.3-1.6 (7H, m), 1.7-1.9 (2H, m), 3.97 (2H, t,J=6.5Hz), 4.38 (2H, q, J=7.lHz), 6.87 (2H, d, J=8.9Hz), 7.44 (2H, d,J=8.9Hz), 7.51 (2H, d, J=8.5Hz), 8.01 (2H, d, J=8.5Hz)

[0183] APCI-MASS : m/z =337 (M+H)+

Preparation 7

[0184] To a solution of 4-(4-n-pentyloxyphenyl)benzamide (1.0 g) intetrahydrofuran (10 ml) was added Lawesson's reagent (1.0 g). Thereaction mixture was refluxed for 3 hours and diluted withdichloromethane. The insoluble residue was removed by filtration and thefiltrate was evaporated to dry. To a solution of the residue intetrahydrofuran (10 ml) was added ethyl bromopyruvate (887 mg). Themixture was stirred for 3 hours at room temperature, diluted withdichloromethane (100 ml) and washed with water and brine. The separatedorganic layer was dried over magnesium sulfate and the solvents wereremoved under reduced pressure. The residue was triturated withacetonitrile and the solid was collected by filtration and dried underreduced pressure to give ethyl4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3- vas thiapentanoate(895 mg).

[0185] IR (KBr) : 3120, 2954, 2863, 1753, 1591, 1498, 1471 cm-l NMR(CDCl₃₁ δ) : 0.94 (3H, t, J=7.OHz), 1.33 (3H, t, J=7.lHz), 1.4-1.6 (4H,m), 1.7-1.9 (2H, m), 3.55 (lH, d, J=12.2Hz), 3.9-4.1 (3H, m), 4.2-4.4(2H, m), 4.47 (lH, s), 6.97 (2H, d, J=8.8Hz), 7.53 (2H, d, J=8.8Hz),7.59 (2H, d, J=8.5Hz), 7.92 (2H, d, J=8.5Hz)

[0186] APCI-MASS m/z =414 (M+H)+

Preparation 8

[0187] To a suspension of ethyl 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-thiapentanoate (0.87 g) in tetrahydrofuran (16ml) and ethanol (8 ml) was added 10% NaOH aq. (1.32 ml). The mixture wasrefluxed for 1 hour and adjusted to pH 2.0 with 1N HCl. The precipitatewas collected by filtration, washed with water and dried under reducedpressure to give crude 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-thiapentanoic acid. A suspension of crude4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3- thiapentanoic acidobtained in ethanol (50 ml) was refluxed for 4 hours. After cooling, theprecipitate was collected by filtration, washed with ethanol and driedunder reduced pressure to give 2-[4-(4-n-pentyloxyphenyl)phenyl]-4-thiazolecarboxylic acid (353 mg).

[0188] IR (KBr) : 2958, 2935, 1687, 1602, 1465, 1253, 1199 cm⁻¹ NMR(DMSO-d₆, 5) * 0.91 (3H, t, J=6.9Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m),4.02 (2H, t, J=6.5Hz), 7.04 (2H, d, J=8.8Hz), 7.69 (2H, d, J=8.8Hz),7.79 (2H, d, J=8.5Hz), 8.02 (2H, d, J=8.5Hz), 8.49 (lH, s), 13.1 (1H, brs)

[0189] APCI-MASS : m/z =368 (M+H)+

[0190] Preparation 9

[0191] To a suspension of 4-n-pentyloxybenzoic acid (5.0 g) in toluenewas added oxalyl chloride (15 ml) and N,N-dimethylformamide (0.1 ml) andthe mixture was stirred for 2 hours at room temperature. The solventswere evaporated under reduced pressure to give crude4-n-pentyloxybenzoyl chloride. To a suspension ofN,O-dimethylhydroxylamine a hydrochloride (3.51 g) and pyridine (5.82ml) in tetrahydrofuran (25 ml) was added the solution of crude4-n-pentyloxybenzoyl chloride in tetrahydrofuran (25 ml) dropwise at 0°C and the mixture was stirred for 3 hours at room temperature. To thereaction mixture 1N HCl was added and extracted with ethyl acetate. Theorganic layer was separated, washed with water and brine, dried overmagnesium sulfate and evaporated under reduced pressure to giveN-(4-n-pentyloxybenzoyl) -N,O-dimethylhydroxylamine (4.63 g).

[0192] NMR (CDC1₃, o) : 0.94 (3H, t, J=7.OHz), 1.3-1.6 (4H, m), 1.7-1.9(2H, m), 3.35 (3H, s), 3.56 (3H, s), 3.99 (2H, t, J=6.5Hz), 6.88 (2H, d,J=8.9Hz), 7.71 (2H, d, J=8.9Hz) APCI-MASS : m/z =252 (M+H)+

[0193] Preparation 10

[0194] To a solution ofN-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.52 g) intetrahydrofuran (25 ml) was added 1.6 molar tetrahydrofuran solution ofvinylmagnesium bromide (25.5 ml) at -50° C dropwise and the mixture wasstirred for 3 hours at -20° C. To the mixture was added 1N HCl (50 ml)dropwise and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified with silicagel column chromatography (hexane/ethyl acetate) =(8/2) to give 1-(4-n-pentyloxyphenyl)acrolein (2.40 g).

[0195] IR (KBr) : 2956, 2935, 2867, 1672, 1600, 1510, 1255, 1170 cm⁻¹NMR (CDCl₃, 5) 0.94 (3H, t, J=7.lHz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m),4.03 (2H, t, J=6.5Hz), 5.86 (1H, dd, J=10.5 and 1.9Hz), 6.42 (1H, dd,J=17.0 and 1.9Hz), 6.94 (2H, d, J=8.9Hz), 7.21 (1H, dd, J=17.0 and10.9Hz), 7.95 (2H, d, J=8.9Hz)

[0196] APCI-MASS m/z =219 (M+H)+

[0197] Preparation 11

[0198] A suspension of 1-(4-n-pentyloxyphenyl)acrolein (2.38 g), methyl4-formylbenzoate (1.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride and triethylamine (0.91 ml) inethanol (10 ml) was refluxed for 18 hours. After cooling, the solventswere removed under reduced pressure. The solids were taken up in 1N HCland extracted with dichloromethane. The organic layer was washedsuccessively with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was triturated withdiisopropyl ether, collected by filtration and dried under reducedpressure to give l-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (3.41 g).

[0199] IR (KBr) : 2956, 2867, 1722, 1672, 1606, 1284, 1257, 1110 cm⁻¹

[0200] NMR (CDC1_(3,) 5) : 0.94 (3H, t, J=7.0Hz), 1.5-1.7 (4H, m),1.8-2.0 (2H, m), 3.44 (4H, s), 3.95 (3H, s), 4.03 (2H, t, J=6.5Hz), 6.94(2H, d, J=8.9Hz), 7.99 (2H, d, J=8.9Hz), 8.08 (2H, d, J=8.7Hz), 8.14(2H, d, J=8.7Hz)

[0201] APCI-MASS : m/z =383 (M+H)+

[0202] Preparation 12

[0203] A suspension of1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl) butane-1,4-dione(765 mg) and phosphorus pentasulfide (533 mg) in tetrahydrofuran (10 ml)was stirred for 6 hours at room temperature, poured into water andstirred for 1 hour. The precipitate was collected by filtration, washedwith water and dried under reduced pressure to give methyl4-[5-(4-n-pentyloxyphenyl)thiophen-2-yl]benzoate (668 mg)

[0204] IR (KBr) 2956, 2935, 2867, 1722, 1604, 1438, 1284, 1112, 1022cm⁻¹

[0205] NMR (CDC1₃, o) : 0.94 (3H, t, J=6.9Hz), 1.3-1.5 (4H, -m), 1.7-1.9(2H, m), 3.93 (3H, s), 3.99 (2H, t, J=6.5Hz), 6.88 (2H, d, J=8.8Hz),7.19 (1H, d, J=3.8Hz), 7.37 (lH, d, J=3.8Hz), 7.55 (2H, d, J=8.8Hz),7.66 (2H, d, J=8.5Hz), 8.04 (2H, d, J=8.5Hz)

[0206] APCI-MASS m/z =381 (M+H)+

[0207] Preparation 13

[0208] A solution of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (765 mg) and p-toluenesulfonic acid monohydrate (8 mg)in toluene (10 ml) was refluxed for 6 hours. The reaction mixture wasdiluted with dichloromethane, washed with water and brine, and driedover magnesium sulfate. The solvents were removed under reduced pressureand the precipitate was triturated with methanol, collected byfiltration, washed with methanol and dried under reduced pressure togive methyl 4-[5-(4-n-pentyloxyphenyl) furan-2-yl]benzoate (665 mg).

[0209] IR (KBr) : 2956, 2933, 1720, 1284, 1253, 1176, 1110 cm⁻¹

[0210] NMR (CDCl₃, 5) : 0.94 (3H, t, J=6.9Hz), 1.3-1.5 (4H, m), 1.7-1.9(2H, m), 3.93 (3H, s), 3.99 (2H, t, J=6.5Hz), 6.62 (1H, d, J=3.5Hz),6.85 (1H, d, J=3.5Hz), 6.94 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8Hz),7.76 (2H, d, J=8.5Hz), 8.05 (2H, d, J=8.5Hz)

[0211] APCI-MASS : m/z =365 (M+H)+

[0212] Preparation 14

[0213] A mixture of 4-cyclohexylcyclohexanone (1.54 g),1-(4-ethoxycarbonylphenyl) piperazine (2 g) and titanium(IV)isopropoxide (3.18 ml) was stirred at room temperature. After 1 hour,the IR spectrum of the mixture showed no ketone band, and the viscoussolution was diluted with absolute ethanol (8.5 ml). Sodiumcyanoborohydride (0.343 g) was added, and the solution was stirred for 3hours. Water (3 ml) was added with stirring, and the resulting inorganic precipitate was filtered and washed with ethanol. The filtratewas extracted with ethyl acetate. The organic layer was taken and driedover magnesium sulfate. The magnesium sulfate was filtered off, andfiltrate was evaporated under reduced pressure. The residue wassubjected to column chromatography on silica gel and eluted with(hexane/ethyl acetate)=(3/1). The fractions containing the less polarcompound were collected and evaporated under reduced pressure to giveethyl 4-[4-(cis-4-cyclohexylcyclohexyl)piperazin-1-yllbenzoate (692 mg)as byproduct. The fractions containing the more polar compound werecollected and evaporated under reduced pressure to give ethyl4-[4-(trans-4-cyclohexylcyclohexyl) piperazin-1-yl]benzoate (587 mg).

[0214] Trans isomer

[0215] IR (KBr) : 2931.3, 1708.6, 1606.4, 1234.2 cm ⁻¹ NMR (CDCi₃, 5) :0.80-1.5 (12H, m), 1.36 (3H, t, J=7.1Hz), 1.5-2.1 (8H, m), 2.40 (1H, m),2.7-2.9 (4H, m), 3.3-3.5 (4H, m), 4.33 (2H, q, J=7.lHz), 6.86 (2H, d,J=9.lHz), 7.92 (2H, d, J=9.lHz)

[0216] APCI-MASS : m/z =m/z =399 (M+H)+

[0217] Cis isomer

[0218] IR (KBr) : 2925.5, 1706.7, 1606.4, 1282.4 cm ⁻¹ NMR (CDC1₃, 5) :0.8-1.9 (20H, m), 1.36 (2H, t, J=7.lHz), 2.25 (1H, m), 2.6-2.8 (4H, m),3.2-3.5 (4H, m), 4.33 (2H, q, J=7.1Hz), 6.85 (2H, d, J=9.lHz), 7.92 (2H,d, J=9.lHz)

[0219] APCI-MASS : m/z =399 (M+H)+

[0220] The following compound was obtained according to a similar mannerto that of Preparation 14.

[0221] Preparation 15

[0222] 4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]benzonitrile

[0223] IR (KBr) 2931.3, 2215.8, 1606, 1515.8, 1178.3 cm ⁻¹ NMR(CDC1_(3,) 5) 1.0-2.6 (23H, m), 2.65-2.95 (2H, m), 2.95-3.25 (2H, m),3.8-4.0 (2H, m), 6.83 (2H, d, J=8.9Hz), 7.46 (2H, d, J=8.9Hz)

[0224] APCI-MASS m/z =352 (M+H)+

[0225] Preparation 16

[0226] To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran(10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) intetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature.Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone(4.12 g) and stirred for 2 hours under ice-cooling. The reaction wasquenched with saturated NH₄Cl aq. and extracted with ethyl acetate. Theorganic layer was taken and dried over magnesium sulfate. The magnesiumsulfate was filtered off, and filtrate was evaporated under reducedpressure. The residue was subjected to column chromatography on silicagel and eluted with (hexane/ethyl acetate) =(3/1). The fractionscontaining the object compound were collected and evaporated underreduced pressure to give1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g).

[0227] IR (KBr) 3430, 1675.8, 1247.7 cm ⁻¹ NMR (CDC1_(3,) d) : 0.90 (3H,t, J=6.6Hz), 1.2-1.85 (11H, m), 1.85-2.1 (2H, m), 3.2-3.5 (2H, m), 3.94(2H, t, J=6.5Hz), 4.05-4.2 (2H, m), 5.15 (2H, s), 6.87 (2H, d, J=8.8Hz),7.3-7.5 (7H, m)

[0228] APCI-MASS : m/z =394 (M+H-H₂0)⁺

[0229] The following compound was obtained according to a similar mannerto that of Preparation 16.

[0230] Preparation 17

[0231] 1-tert-Butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine

[0232] IR (KBr) : 3434.6, 2954.4, 2931.3, 1693.2, 1670.1, 1172.5 cm ⁻¹NMR (CDC1₃, 5) : 0.90 (3H, t, J=6.5Hz), 1.2-1.5 (8H, m), 1.49 (9H, s),1.65-1.85 (4H, m), 1.85-2.1 (2H, m), 3.1-3.35 (2H, m), 4.10 (2H, t,J=7.lHz), 4.17 (1H, br s), 6.88 (2H, d, J=8.9Hz), 7.37 (2H, d, J=8.9Hz)

[0233] Preparation 18

[0234] To a solution of 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (1.4 g) in methanol (28 ml) was added dry 10%palladium on carbon (0.7 g) and stirred for 6 hours under hydrogenatmosphere. The palladium on carbon was filtered off, and the filtratewas evaporated under reduced pressure to give4-(4-hexyloxyphenyl)-4-hydroxypiperidine (0.74 g).

[0235] IR (KBr) : 3332.4, 1610.3, 1513.8, 1249.6 cm ⁻¹ NMR (CDC1₃, 8) :0.90 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.6-1.9 (4H, m), 1.9-2.19 (2H,m), 2.35 (2H, br s), 2.85-3.25 (4H, m), 3.95 (2H, t, J=6.5Hz), 6.87 (2H,d, J=8.8Hz), 7.40 (2H, d, J=8.8Hz)

[0236] APCI-MASS : m/z =260 (M+H-H₂0)+

[0237] The following compounds [Preparations 19 and 201 were obtainedaccording to a similar manner to that of Preparation 18.

[0238] Preparation 19

[0239] 4-[4-(4-Hexyloxyphenyl)-4-hydroxypiperidin-1-yl]benzoic acid IR(KBr) : 3548.4, 1668.1, 1600.6, 1187.9 cm ¹ 20 NMR (DMSO-d₆, o) : 0.87(3H, t, J=6.5Hz), 1.2-1.5 (6H, m), 1.6-1.8 (4H, m), 1.8-2.1 (2H, m),3.1-3.4 (2H, m), 3.7-3.85 (2H, m), 3.92 (2H, t, J=6.5Hz), 4.97 (1H, s),6.85 (2H, d, J=8.8Hz), 6.99 (2H, d, J=9.OHz), 7.35 (2H, d, J=8.8Hz),7.76 (2H, d, J=9.OHz), 12.2 (1H, s) APCI-MASS : m/z =398 (M+H)⁺

[0240] Preparation 20

[0241] Ethyl 4- [4-(4-hexyloxyphenyl)piperidin-1-yllbenzoate

[0242] IR (KBr) : 1700.9, 1606.4, 1511.9, 1274.7, 1178.3 cm 1 NMR(CDCl₃, o) : 0.90 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.40 (3H, t,J=7.2Hz), 1.7-2.1 (6H, m), 2.5-2.8 (1H, m), 2.8-3.05 (2H, m), 3.93 (2H,t, J=6.5Hz), 3.9-4.1 (2H, m), 4.32 (2H, q, J=7.2Hz), 6.84 (2H, d,J=8.7Hz), 6.90 (2H, d, J=9.OHz), 7.12 (2H, d, J=8.7Hz), 7.92 (2H, d,J=9.OHz) APCI-MASS m/z =410 (M+H)+

[0243] Preparation 21

[0244] To a solution of methyl 3-(4-n-hexyloxyphenyl)propionate (1.18 g)in ethanol (10 ml) was added hydrazine monohydrate (1.08 ml) and themixture was refluxed for 24 hours. After cooling, the solvent wasremoved under reduced pressure. Water was added and the precipitate wascollected by filtration, washed with water and dried under reducedpressure to give 3-(4-n-hexyloxyphenyl)propionohydrazide (0.92 g).

[0245] IR (KBr) : 3317, 2929, 1625, 1513, 1245 cm ⁻¹ NMR (DMSO-d₆, o) :0.87 (3H, t, J=6.4Hz), 1.3-1.5 (6H, m), 1.6-1.8 (2H, m), 2.26 (2H, t,J=7.7Hz), 2.72 (2H, t, J=7.7Hz), 3.90 (2H, t, J=6.5Hz), 4.14 (2H, d,J=4.2Hz), 6.80 (2H, d, J=8.6Hz), 7.07 (2H, d, J=8.6Hz), 8.93 (lH, t,J=4.2Hz)

[0246] APCI-MASS : m/z 265 (M+H)⁺

[0247] The following compounds [Preparations 22 and 23] were obtainedaccording to a similar manner to that of Preparation 21.

[0248] Preparation 22

[0249] N-(tert-Butoxycarbonyl)isonipecotinohydrazide

[0250] IR (KBr) : 3320, 2979, 2942, 2846, 1691, 1629, 1527, 1432, 1230,1178 cm ⁻¹ NMR (DMSO-d₆, 5) 1.39 (9H, s), 1.3-1.7 (4H, m), 2.1- 2.3 (lH,m), 2.69 (2H, t, J=11.9Hz), 3.93 (2H, d, J=13.2Hz), 4.15 (2H, s), 8.99(lH, s)

[0251] APCI-MASS : m/z =144 (M-Boc)+

[0252] Preparation 23

[0253] 4-(3-Phenoxypropyloxy)benzohydrazide

[0254] IR (KBr): 3297, 3182, 2948, 1650, 1502, 1305, 1253 cm ⁻¹ NMR(DMSO-d₆, 5) : 2.18 (2H, tt, J=6.2 and 6.2Hz), 4.12 (2H, t, J=6.2Hz),4.18 (2H, t, J=6.2Hz), 4.41 (2H, s), 6.9-7.1 (5H, m), 7.2-7.4 (2H, m),7.79 (2H, d, J=8.8Hz), 9.60 (1H, s)

[0255] APCI-MASS : m/z =287 (M+H)+

[0256] Preparation 24

[0257] To a suspension of 1-acetyl-4-(4-hydroxyphenyl) piperazine (20 g)and potassium bicarbonate (12.55 g) in dimethylsulfoxide (200 ml) wasadded 1-bromohexane (19.12 ml) and stirred for 24 hours at 80° C. Thereaction mixture was added to a mixture of water and ethyl acetate. Theorganic layer was taken and dried over is magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure to give 1-acetyl-4-(4-hexyloxyphenyl)piperazine(14.5 g).

[0258] IR (KBr) : 1621.8, 1513.8, 1251.6, 825.4 cm ¹ NMR (CDC1₃₁ o) :0.90 (3H, t, J=6.4Hz), 1.25-1.55 (6H, m), 1.65-1.85 (2H, m), 2.13 (3H,s), 3.02 (2H, t, J=5.2Hz), 3.04 (2H, t, J=5.2Hz), 3.61 (2H, t, J=5.2Hz),3.76 (2H, t, J=5.2Hz), 3.91 (2H, t, J=6.5Hz), 6.83 (2H, d, J=9.lHz),6.89 (2H, d, J=9.lHz)

[0259] The following compounds [Preparations 25 to 27] were obtainedaccording to a similar manner to that of Preparation 24.

[0260] Preparation 25

[0261] 4-[4-(4-Hexyloxyphenyl)piperazin-1-yllbenzonitrile IR (KBr) :2212.0, 1602.6, 1510.0, 1247.7, 827.3 cm ⁻¹ NMR (CDCl₃, o) : 0.90 (3H,t, J=6.5Hz), 1.2-1.6 (6H, m), 1.65-1.9 (2H, m), 3.1-3.3 (4H, m), 3.4-3.6(4H, m), 3.92 (2H, t, J=6.5Hz), 6.8-7.0 (6H, m), 7.52 (2H, d, J=9.OHz)

[0262] APCI-MASS : m/z =364 (M+H)+

[0263] Preparation 26

[0264] Methyl 4-(3-phenoxypropyloxy)benzoate

[0265] IR (KBr) : 2944, 2885, 1722, 1604, 1500, 1247 cm ⁻¹ NMR (CDC1₃,5) : 2.28 (2H, tt, J=6.0 and 6.0Hz), 3.88 (3H, s), 4.16 (2H, t,J=6.0Hz), 4.21 (2H, t, J=6.0Hz), 6.8-7.0 (5H, m), 7.2-7.4 (2H, m), 7.98(2H, d, J=9.OHz)

[0266] APCI-MASS m/z =287 (M+H)+

[0267] Preparation 27

[0268] Methyl4-[5-(1-n-octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]benzoate

[0269] IR (KBr) : 2925, 2852, 1714, 1440, 1278 cm ⁻¹ NMR (CDC1₃, o) :0.89 (3H, t, J=6.5Hz), 1.2-1.4 (1OH, m), 1.4-2.4 (1OH, m), 3.0-3.1 (2H,m), 3.2-3.3 (1H, m), 3.95 (3H, s), 8.01 (2H, d, J=8.6Hz), 8.13 (2H, d,J=8.6Hz)

[0270] APCI-MASS : m/z =416 (M+H)+

[0271] Preparation 28

[0272] A solution of 1-acetyl-4-(4-hexyloxyphenyl)piperazine (14 g) in1N HCl was refluxed for 5 hours. The reaction mixture was adjusted to pH8 with saturated Na₂CO₃ aq. and extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was evaporated under reducedpressure. To the residue was added ethyl acetate and 4N HCl in ethylacetate (23 ml) and stirred for 1 hour. The resulting precipitate wascollected by filtration to give 1-(4-hexyloxyphenyl) piperazinedihydrochloride (8.669 g).

[0273] IR (KBr) : 1604.5, 1513.8, 1259.3 cm ⁻¹ NMR (DMSO-d₆, 5) : 0.874(3H, t, J=6.6Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.2-3.55 (8H, m),3.92 (2H, t, J=6.4Hz), 6.92 (2H, d, J=9.lHz), 7.15 (2H, d, J=9.lHz),8.27 (1H, br s), 9.61 (2H, br s)

[0274] APCI-MASS : m/z =263 (M+H)+

[0275] The following compound was obtained according to a similar mannerto that of Preparation 28.

[0276] Preparation 29

[0277] 1-(4-Cyclohexyloxyphenyl)piperazine dihydrochloride

[0278] Preparation 30

[0279] To a suspension of 1-(4-hexyloxyphenyl)piperazine dihydrochloride(0.914 g) and potassium bicarbonate (0.564 g) in dimethylsulfoxide (5ml) was added ethyl p-fluorobenzoate (0.2 ml) and stirred for 10 hoursat 150° C. The reaction mixture was added to a mixture of water andethyl acetate. The organic layer was taken and dried over magnesiumsulfate. The magnesium sulfate was filtered off, and the filtrate wasevaporated under reduced pressure to give ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (0.347 g).

[0280] IR (KBr) 1710.6, 1606.4, 1511.9, 1286.3, 1224.6 cm ⁻¹ NMR (CDC1₃,5) : 0.90 (3H, t, J=6.5Hz), 1.2-1.55 (6H, m), 1.37 (3H, t, J=7.lHz),1.65-1.85 (2H, m), 3.1-3.25 (4H, m), 3.4-3.55 (4H, m), 3.92 (2H, t,J=6.5Hz), 4.33 (2H, q, J=7.lHz), 6.8-7.0 (6H, m), 7.95 (2H, d, J=9.OHz)

[0281] The following compounds [Preparations 31 to 38] were obtainedaccording to a similar manner to that of Preparation 30.

[0282] Preparation 31

[0283] Methyl 4-[4-(4-cyclohexylphenyl)piperazin-1-yl]methylbenzoate

[0284] IR (KBr) : 2925.5, 1720.2, 1276.6, 1108.9 cm ⁻¹ NMR (CDC1₃, 5) :1.1-2.0 (10H, m), 2.42 (lH, m), 2.5-2.7 (4H, m), 3.1-3.3 (4H, m), 3.61(2H, s), 3.91 (3H, s), 6.85 (2H, d, J=8.7Hz), 7.10 (2H, d, J=8.7Hz),7.43 (2H, d, J=8.2Hz), 8.00 (2H, d, J=8.2Hz)

[0285] Preparation 32

[0286] Ethyl 4-[4-(4-cyclohexyloxyphenyl)piperazin-1-yl]benzoate

[0287] Preparation 33

[0288] 3-[2-(4-Morpholinophenylamino)ethyl]-2-oxazolidone

[0289] IR (KBr) : 3330.5, 1740, 1523.5, 1118.5 cm ⁻¹ NMR (CDCl₃, 5) :2.9-3.2 (4H, m), 3.2-3.7 (4H, m), 3.60 (2H, dd, J=8.3 and 6.5Hz),3.8-4.0 (4H, m), 4.29 (2H, dd, J=8.9 and 7.1Hz), 6.5-6.7 (2H, m),6.8-7.0 (2H, m)

[0290] APCI-MASS : m/z 292 (M+H)⁺

[0291] Preparation 34

[0292] 4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzonitrile IR (KBr) :2210.0, 1600.6, 1511.9, 1234.2 cm ¹ NMR (CDC1₃, 5) : 3.2-3.15 (4H, m),3.15-3.3 (4H, m), 3.4-3.55 (4H, m), 3.8-3.9 (4H, m), 6.8-7.0 (6H, m),7.52 (2H, d, J=9.OHz)

[0293] APCI-MASS : m/z =349 (M+H)+

[0294] Preparation 35

[0295] Diphenylmethyl 4-[4-(4-hexyloxyphenyl)-4-hydroxypiperidin-1-yl]benzoate

[0296]1IR (KBr) : 3463.5, 1681.6, 1604.5, 1184.1 cm ⁻¹ NMR (CDC1₃, 5) :0.90 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.65-1.95 (4H, m), 2.0-2.3 (2H,m), 3.3-3.5 (2H, m), 3.65-3.85 (2H, m), 3.95 (2H, t, J=6.5Hz), 6.88 (2H,d, J=8.9Hz), 6.8-7.0 (2H, m), 7.09 (1H, s), 7.2-7.5 (10H, m), 8.03 (2H,d, J=8.9Hz)

[0297] APCI-MASS m/z =564 (M+H)+

[0298] Preparation 36

[0299] Ethyl4-[4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl]benzoate

[0300] IR (KBr) : 2931.3, 1706.7, 1608.3, 1515.8 cm ⁻¹ NMR (CDC1₃, 5) :0.91 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.37 (3H, t, J=7.lHz), 1.7-1.9(2H, m), 2.67 (2H, m), 3.63 (2H, t, J=5.6Hz), 3.96 (2H, m, J=6.5Hz),3.9-4.1 (2H, m), 4.32 (2H, q, J=7.lHz), 6.0-6.1 (1H, m), 7.34 (2H, d,J=8.8Hz), 7.94 (2H, d, J=8.8Hz)

[0301] FAB-MASS m/z =406 (M+H)+

[0302] Preparation 37

[0303] 4-[4-(3-Methoxyphenyl)piperazin-1-yllbenzonitrile

[0304] IR (KBr) 2829.1, 2213.9, 1604.5, 1174.4 cm ⁻¹ NMR (CDC1₃, 5) :3.3-3.4 (4H, m), 3.4-3.55 (4H, m), 3.81 (3H, s), 6.46 (1H, d, J=9.OHz),6.49 (1H, s), 6.56 (1H, d, J=9.OHz), 6.90 (2H, d, J=9.OHz), 7.13 (1H,dd, J=9.OHz), 7.52 (2H, d, J=9.OHz)

[0305] Preparation 38

[0306] 4-[4-(Piperidin-4-yl)piperidin-1-yl]benzonitrile

[0307] IR (KBr) : 3332.4, 2212.0, 1602.6, 1513.8, 1178 cm ⁻¹ NMR (CDC1₃,o) : 1.0-1.5 (6H, m), 1.6-2.0 (4H, m), 1.91 (1H, s), 2.5-2.7 (2H, m),2.7-2.9 (2H, m), 3.0-3.2 (2H, m), 3.8-4.0 (2H, m), 6.84 (2H, d,J=9.OHz), 7.45 (2H, d, J=9.OHz)

[0308] APCI-MASS : m/z =270 (M+H)⁺

[0309] Preparation 39

[0310] A solution of 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]-benzonitrile(0.582 g) in the mixture of conc. HCl (5.8 ml) and acetic acid (2.9 ml)was refluxed for 3 hours. The reaction mixture was pulverized with water(25 ml). The precipitate was collected by filtration to give4-[4-(4-hexyloxyphenyl) piperazin-l-yl]benzoic acid hydrochloride (0.51g).

[0311] IR (KBr) : 1726.0, 1699.0, 1606.4, 1511.9 cm ⁻¹ NMR (DMSO-d₆, 5): 0.88 (3H, t, J=6.5Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.5-3.9 (8H,m), 4.00 (2H, t, J=6.4Hz), 7.07 (2H, d, J=8.9Hz), 7.09 (2H, d, J=8.9Hz),7.61 (2H, d, J=8.9Hz), 7.84 (2H, d, J=8.9Hz)

[0312] APCI-MASS m/z =383 (M+H)⁺

[0313] The following compounds [Preparations 40 to 42] were obtainedaccording to a similar manner to that of Preraration 39.

[0314] Preparation 40

[0315] 4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzoic aciddihydrochloride

[0316] IR (KBr) : 1706.7, 1602.6, 1513.8, 1232.3 cm ⁻¹ NMR (DMSO-d₆, 5)2.9-3.0 (4H, m), 3.1-3.2 (4H, m), 3.3-3.5 (4H, m), 3.65-3.8 (4H, m),6.87 (2H, d, J=8.7Hz), 6.93 (2H, d, J=8.7Hz), 7.02 (2H, d, J=9.OHz),7.79 (2H, d, J=9.OHz)

[0317] APCI-MASS : m/z =368 (M+H)⁺

[0318] Preparation 41

[0319] 4-[4-(3-Hydroxyphenyl)piperazin-1-yl]benzoic acid dihydrobromide

[0320] IR (KBr) : 3183.9, 1679.7, 1604.5, 1232.3 cm ⁻¹ NMR (DMSO-d₆l 5): 3.3-3.7 (8H, m), 6.45 (1H, d, J=7.9Hz), 6.62 (lH, d, J=7.9Hz), 6.68(1H, s), 7.04 (2H, d, J=9.OHz), 7.13 (lH, dd, J=7.9Hz), 7.81 (2H, d,J=9.OHz) APCI-MASS : m/z =299 (M+H)⁺

[0321] Preparation 42

[0322] 4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]benzoic aciddihydrobromide

[0323] IR (KBr) : 1668.1, 1606, 1186 cm ⁻¹ NMR (DMSO-d₆, o) 1.0-2.3(21H, m), 2.7-4.1 (8H, m), 6.94 (2H, d, J=8.6Hz), 7.76 (2H, d, J=8.6Hz)

[0324] APCI-MASS : m/z 371 (M+H)⁺

[0325] Preparation 43

[0326] To a solution of ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (2.19 g) in the mixture of ethanol (22 ml)andtetrahydrofuran (22 ml) was added 2N NaOH aq. and refluxed for 5 hours.The reaction mixture was adjusted to pH 1-1.5 with 1N HCl and theresulting precipitate was collected by filtration to give4-[4-(4-hexyloxyphenyl)piperazin-1- yl]benzoic acid hydrochloride (1.99g).

[0327] IR (KBr) 1664.3, 1600.6, 1511.9, 1230.4 cm ¹ NMR (DMSO-d₆, 5) :0.88 (3H, t, J=6.5Hz), 1.2-1.5 (6H, nm), 1.55-1.8 (2H, m), 3.0-3.6 (8H,m), 3.88 (2H, t, J=6.4Hz) 6.83 (2H, d, J=9.2Hz), 6.94 (2H, d, J=9.2Hz),7.01 (2H, d, J=8.9Hz), 7.78 (2H, d, J=8.9Hz)

[0328] The following compounds [Preparations 44 to 60] were obtainedaccording to a similar manner to that of Preparation 43.

[0329] Preparation 44

[0330] 4-[4-(trans-4-Cyclohexylcyclohexyl)piperazin-1-yllbenzoic acidhydrochloride

[0331] IR (KBr) : 2919.7, 2852.2, 1695.1, 1606.4, 1234.2 cm ⁻¹ NMR(DMSO-d₆l 5) : 0.8-2.0 (20H, m), 2.12 (1H, m), 2.9-3.6 (8H, m), 7.03(2H, d, J=9.OHz), 7.81 (2H, d, J=9.OHz)

[0332] APCI-MASS m/z =371 (M+H)⁺

[0333] Preparation 45

[0334] 4-[4-(cis-⁴-Cyclohexylcyclohexyl)piperazin-1-yl]benzoic acidhydrochloride

[0335] IR (KBr) : 1693.2, 1604.5, 1232.3, 1186.0 cm ⁻¹ NMR (DMSO-d₆, 5): 0.8-2.0 (21H, m), 3.2-3.3 (8H, m), 7.03 (2H, d, J=9.OHz), 7.80 (2H, d,J=9.OHz)

[0336] APCI-MASS m/z 371 (M+H)⁺

[0337] Preparation 46

[0338] 4-[4-(⁴-Cyclohexylphenyl)piperazin-1-yl3methylbenzoic acidhydrochloride

[0339] IR (KBr) 2925.5, 1704.8, 1251.6 cm ⁻¹

[0340] Preparation 47

[0341] 4-[4-(4-Cyclohexyloxyphenyl)piperazin-1-yl]benzoic acidhydrochloride

[0342] Preparation 48

[0343] 4-[4-(4-Hexyloxyphenyl)piperidin-1-yl]benzoic acid IR (KBr)1670.1, 1602.6, 1513.8, 1394.3, 1216.9 cm ⁻¹ NMR (DMSO-d₆, 5) : 0.87(3H, t, J=6.5Hz), 1.2-1.5 (6H, m), 1.5-1.9 (6H, m), 2.55-3.0 (3H, m),3.95 (2H, t, J=6.SHz), 3.9-4.0 (2H, m), 6.84 (2H, d, J=8.7Hz), 6.92 (2H,d, J=8.9Hz), 7.15 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.9Hz)

[0344] APCI-MASS :m/z =382 (M+H)⁺

[0345] Preparation 49

[0346] 4-[4-(4-Hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1- yl]benzoicacid

[0347] IR (KBr) : 1668.1, 1602.6, 1513.8, 1230.4 cm ⁻¹ NMR (DMSO-d₆, 5): 0.88 (3H, m), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 2.5-2.7 (2H, m),3.5-3.7 (2H, m), 3.8-4.1 (4H, m), 6.18 (1H, m), 6.90 (2H, d, J=8.8Hz),6.97 (2H, d, J=8.OHz), 7.40(2H, d, J=8.8Hz), 7.78 (2H, d, J=8.OHz)

[0348] APCI-MASS : m/z =380 (M+H)⁺

[0349] Preparation 50

[0350] 4-(4-n-Pentyloxyphenylethynyl)benzoic acid

[0351] IR (KBr) : 2958, 2931, 1685, 1598, 1513, 1425, 1286, 1247 cm ⁻¹NMR (DMSO-d₆, 5) : 0.90 (3H, t, J=7.OHz), 1.3-1.5 (4H, m), 1.7-1.9 (2H,m), 4.01 (2H, t, J=6.5Hz), 6.99 (2H, d, J=8.8Hz), 7.51 (2H, d, J=8.8Hz),7.62 (2H, d, J=8.3Hz), 7.95 (2H, d, J=8.3Hz), 13.1 (1H, br s)

[0352] APCI-MASS m/z 309 (M+H)⁺

[0353] Preparation 51

[0354] 4-[5-[2-(4-n-Hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2- yl]benzoicacid

[0355] IR (KBr) 2935, 1679, 1513, 1241 cm ¹ NMR (DMSO-d₆, 5) 0.87 (3H,t, J=6.5Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.03 (2H, t, J=7.5Hz),3.44 (2H, t, J=7.5Hz), 3.91 (2H, t, J=6.5Hz), 6.84 (2H, d, J=8.6Hz),7.18 (2H, d, J=8.6Hz), 8.03 (2H, d, J=8.9Hz), 8.08 (2H, d, J=8.9Hz)

[0356] APCI-MASS : m/z =411 (M+H)⁺

[0357] Preparation 52

[0358] 4-[5-(4-n-Pentylphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid

[0359] IR (KBr) : 2954, 2923, 2854, 1685, 1604, 1429, 1288 cm ⁻¹ NMR(DMSO-d₆, 5) : 0.87 (3H, t, J=6.6Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, in),2.67 (2H, t, J=7.6Hz), 7.42 (2H, d, J=8.2Hz), 7.95 (2H, d, J=8.2Hz),8.11 (4H, s)

[0360] APCI-MASS : m/z =353 (M+H)⁺

[0361] Preparation 53

[0362] 4-[5-(4-n-Hexylphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid

[0363] IR (KBr) : 2954, 2921, 2852, 1685, 1429, 1290 cm ⁻¹ NMR (DMSO-d₆,5) : 0.93 (3H, t, J=6.7Hz), 1.2-1.8 (8H, m), 2.73 (2H, t, J=7.7Hz), 7.48(2H, d, J=8.2Hz), 8.01 (2H, d, J=8.lHz), 8.19 (4H, s)

[0364] APCI-MASS m/z =367 (M+H)⁺

[0365] Preparation 54

[0366] 4-[5-(4-n-Heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid

[0367] IR (KBr) : 2923, 2856, 1689, 1604, 1430, 1292, 1250 cm ⁻¹ NMR(DMSO-d₆, o) 0.88 (3H, t, J=6.5Hz), 1.2-1.5 (8H, m), 1.6-1.8 (2H, m),4.07 (2H, t, J=6.5Hz), 7.13 (2H, d, J=8.8Hz), 7.97 (2H, d, J=8.8Hz),8.12 (4H, s)

[0368] APCI-MASS m/z 397 (M+H)⁺

[0369] Preraration 55

[0370] 4-[5-(4-n-Butoxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid

[0371] IR (KBr) 2958, 2869, 1687, 1604, 1432, 1294, 1251, 1174 cm-1

[0372] NMR (DMSO-d₆, 5) : 0.95 (3H, t, J=7.3Hz), 1.4-1.6 (2H, m),1.7-1.9 (2H, m), 4.08 (2H, t, J=7.4Hz), 7.13 (2H, d, J=8.8Hz), 7.97 (2H,d, J=8.8Hz), 8.12 (4H, s )

[0373] APCI-MASS : m/z =355 (M+H)⁺

[0374] Preparation 56

[0375] 4-[5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid

[0376] IR (KBr) : 1687, 1604, 1517, 1430, 1292, 1253, 1178 cm- NMR(DMSO-d₆, o) 3.86 (3H, s), 7.14 (2H, d, J=8.9Hz), 7.98 (2H, d, J=8.9Hz),8.12 (4H, s), 13.26 (1H, br s)

[0377] APCI-MASS : m/z =313 (M+H)⁺

[0378] Preparation 57

[0379] 4-[5-[4-(3-Phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid

[0380] IR (KBr) : 2948, 1689, 1602, 1411, 1292, 1243, 1174 cm ⁻¹ NMR(DMSO-d₆, o) : 2.22 (2H, tt, J=6.2 and 6.2Hz), 4.15 (2H, t, J=6.2Hz),4.26 (2H, t, J=6.2Hz), 6.9-7.0 (3H, m), 7.17 (2H, d, J=8.9Hz), 7.2-7.4(2H, m), 7.98 (2H, d, J=8.9Hz), 8.12 (4H, s)

[0381] APCI-MASS m/z =433 (M+H)⁺

[0382] Preparation 58

[0383] 4-[5-(1-n-Octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]- benzoicacid hydrochloride

[0384] IR (KBr) 2933, 2871, 1714, 1438, 1278, 1110 cm i NMR (DMSO-d₆, 5): 0.87 (3H, t, J=0.9Hz), 1.2-1.5 (10H, m), 1.6-2.4 (4H, m), 3.0-3.2 (2H,m), 3.3-3.4 (1H, m), 3.4-4.0 (4H, m), 8.10 (4H, s), 11.67 (1H, s)

[0385] APCI-MASS : m/z =402 (M+H)⁺

[0386] Preparation 59

[0387] 4-[5-(4-n-Pentyloxyphenyl)thiophen-2-yl]benzoic acid

[0388] IR (KBr) : 2956, 2935, 2867, 1685, 1604, 1288, 1251, 1182 cm-1NMR (DMSO-d₆, o) : 0.90 (3H, t, J=6.9Hz), 1.3-1.5 (4H, m), 1.6-1.8 (2H,m), 4.01 (2H, t, J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.41 (1H, d, J=3.5Hz),7.5-7.7 (3H, m), 7.78 (2H, d, J=8.5Hz), 7.95 (2H, d, J=8.5Hz)

[0389] APCI-MASS : m/z =367 (M+H)⁺

[0390] Preparation 60

[0391] 4-[5-(4-n-Pentyloxyphenyl)furan-2-yl]benzoic acid IR (KBr) :2958, 2935, 1681, 1608, 1538, 1294, 1253 cm ⁻¹ NMR (DMSO-d₆f 5) : 0.91(3H, t, J=6.9Hz), 1.3-1.5 (4H, m), 1.6-1.8 (2H, m), 4.01 (2H, t,J=6.4Hz), 6.96 (1H, d, J=3.5Hz), 7.02 (2H, d, J=8.8Hz), 7.19 (lH, d,J=3.5Hz), 7.76 (2H, d, J=8.8Hz), 7.85 (2H, d, J=8.5Hz), 7.98 (2H, d,J=8.5Hz)

[0392] APCI-MASS : m/z =351 (M+H)⁺

[0393] Preparation 61

[0394] To a suspension of 3-(4-n-hexyloxyphenyl)propiono-hydrazide (0.92g) in tetrahydrofuran (25 ml) and pyridine (0.84 ml) was added asolution of 4-methoxycarbonylbenzoyl chloride (0.73 g) intetrahydrofuran (10 ml) dropwise at 5° C. The reaction mixture wasstirred for 1 hour and poured into ice-water. The precipitate wascollected by filtration, washed with water and dried under reducedpressure to give1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.43 g).

[0395] IR (KBr) 3234, 2929, 1724, 1689, 1646, 1515, 1282, 1108 cm ⁻¹ NMR(DMSO-d₆l 5) : 0.87 (3H, t, J=6.4Hz), 1.3-1.5 (6H, m), 1.6-1.8 (2H, m),2.4-2.5 (2H, m), 2.81 (2H, d, J=7.7Hz), 3.89 (3H, s), 3.91 (2H, t,J=6.5Hz), 6.83 (2H, d, J=8.6Hz), 7.15 (2H, d, J=8.6Hz), 7.98 (2H, d,J=8.5Hz), 8.07 (2H, d, J=8.5Hz), 9.97 (lH, s), 10.51 (1H, s)

[0396] APCI-MASS : m/z =427 (M+H)⁺

[0397] The following compounds [Preparations 62 to 68] were obtainedaccording to a similar manner to that of Preparation 61.

[0398] Preparation 62

[0399] 1-(4-Methoxycarbonylbenzoyl)-2-(4-n-pentylbenzoyl)-hydrazine

[0400] IR (KBr) : 2958, 2929, 1724, 1685, 1646, 1282 cm ⁻¹ NMR (DMSO-d₆,5) : 0.86 (3H, t, J=6.7Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m), 2.65 (2H,t, J=6.8Hz), 3.90 (3H, s), 7.34 (2H, d, J=8.lHz), 7.84 (2H, d, J=8.lHz),8.05 (2H, d, J=3.4Hz), 8.07 (2H, d, J=3.4Hz), 10.50 (1H, s), 10.69 (1H,s)

[0401] APCI-MASS : m/z =369 (M+H)⁺

[0402] Preparation 63

[0403] 1-[N-(tert-Butoxycarbonyl)piperidin-4-yl)carbonyl]-2-(4-methoxycarbonylbenzoyl)hydrazine

[0404] IR (KBr) : 3291, 2940, 1727, 1664, 1540, 1436, 1278 cm ⁻¹ NMR(DMSO-d₆, 5) : 1.41 (9H, s), 1.4-1.9 (4H, m), 2.3- 2.5 (1H, m), 2.79(2H, t, J=11.5Hz), 3.89 (3H, s), 3.96 (2H, d, J=13.5Hz), 7.97 (2H, d,J=8.6Hz), 8.06 (2H, d, J=8.6Hz), 9.96 (1H, s), 10.50 (1H, s) 20APCI-MASS : m/z =306 (M-Boc)

[0405] Preparation 64

[0406] 1-(4-Methoxycarbonylbenzoyl)-2-[4-(3-phenoxypropyloxy)-benzoyl]hydrazine

[0407] IR (KBr) : 3228, 2950, 2883, 1722, 1685, 1645, 1604, 1465, 1280,1247 cm ⁻¹ NMR (DMSO-d₆, 5) : 2.21 (2H, tt, J=6.2 and 6.2Hz), 3.91 (3H,s), 4.15 (2H, t, J=6.2Hz), 4.23 (2H, t, J=6.2Hz), 6.9-7.1 (3H, m), 7.08(2H, d, J=8.8Hz), 7.29 (2H, dd, J=8.8 and 7.2Hz), 7.91 (2H, d, J=8.8Hz),8.03 (2H, d, J=8.6Hz), 8.10 (2H, d, J=8.6Hz), 10.42 (1H, S), 10.63 (1H,s)

[0408] APCI-MASS : m/z =449 (M+H)⁺

[0409] Preparation 65

[0410] 1-(4-Methoxybenzoyl)-2-(4-methoxycarbonylbenzoyl)- hydrazine

[0411] IR (KBr) 3267, 3068, 1722, 1679, 1643, 1610, 1558, 1506, 1284,1257 cm ⁻¹ NMR (DMSO-d₆, 5) : 3.84 (3H, s), 3.90 (3H, s), 7.06 (2H, d,J=8.9Hz), 7.92 (2H, d, J=8.9Hz), 8.03 (2H, d, J=8.7Hz), 8.10 (2H, d,J=8.7Hz), 10.42 (1H, s), 10.63 (lH, s)

[0412] APCI-MASS : m/z =329 (M+H)⁺

[0413] Preparation 66

[0414] 1-(4-n-Butoxybenzoyl)-2-(4-methoxycarbonylbenzoyl)- hydrazine

[0415] IR (KBr) : 3305, 2956, 1724, 1683, 1643, 1610, 1284, 1251, 1184,1108 cm ⁻¹ NMR (DMSO-d₆, 5) 0.94 (3H, t, J=7.3Hz), 1.4-1.6 (2H, nm),1.6-1.8 (2H, m), 3.90 (3H, s), 4.06 (2H, t, J=6.4Hz), 7.05 (2H, d,J=8.8Hz), 7.90 (2H, d, J=8.8Hz), 8.03 (2H, d, J=8.6Hz), 8.10 (2H, d,J=8.6Hz), 10.42 (1H, s), 10.64 (iH, s)

[0416] APCI-MASS : m/z =371 (M+H)⁺

[0417] Preparation 67

[0418] 1-(4-n-Heptyloxybenzoyl)-2-(4-methoxycarbonylbenzoyl)- hydrazine

[0419] IR (KBr) 3237, 2929, 2858, 1726, 1683, 1643, 1610, 1284, 1253 cm⁻¹ NMR (DMSO-d₆, 5) 0.87 (3H, t, J=6.5Hz), 1.2-1.5 (8H, m), 1.6-1.8 (2H,m), 3.90 (3H, s), 4.04 (2H, d, J=6.4Hz), 7.04 (2H, d, J=8.8Hz), 7.90(2H, d, J=8.8Hz), 8.03 (2H, d, J=8.6Hz), 8.10 (2H, d, J=8.6Hz), 10.42(1H, s), 10.64 (1H, s)

[0420] APCI-MASS m/z =413 (M+H)⁺

[0421] Preparation 68

[0422] 1-(4-n-Hexylbenzoyl)-2-(4-methoxycarbonylbenzoyl)- hydrazine

[0423] IR (KBr) : 3330, 2958, 2925, 2854, 1726, 1685, 1647, 1282, 1108cm ⁻¹ NMR (DMSO-d₆, 5) : 0.86 (3H, t, J=6.6Hz), 1.2-1.4 (6H, m), 1.5-1.7(2H, m), 2.65 (2H, t, J=7.5Hz), 3.90 (3H, s), 7.34 (2H, d, J=8.2Hz),7.84 (2H, d, J=8.2Hz), 8.0-8.2 (4H, m), 10.50 (lH, s), 10.68 (1H, s)

[0424] APCI-MASS : m/z =383 (M+H)⁺

[0425] Preparation 69

[0426] A suspension of1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.0 g) and diphosphorus pentasulfide (730 mg) intetrahydrofuran (20 ml) was stirred for 1 hour at 60° C. To a reactionmixture was added water and the mixture was stirred for 1 hour at roomtemperature. The precipitate was collected by filtration, washed withwater and dried under reduced pressure to give methyl4-[5-[2-(4-n-hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoate (883mg).

[0427] IR (KBr) 2927, 1724, 1513, 1280, 1108 cm ⁻¹ NMR (CDC1₃, 6) 0.90(3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m), 3.11 (2H, t,J=7.6Hz), 3.46 (2H, t, J=7.6Hz), 3.93 (2H, t, J=6.5Hz), 3.95 (3H, s),6.84 (2H, d, J=8.6Hz), 7.14 (2H, d, J=8.6Hz), 7.98 (2H, d, J=8.4Hz),8.12 (2H, d, J=8.4Hz)

[0428] APCI-MASS m/z =425 (M+H)⁺

[0429] The following compounds [Preparations 70 to 76] were obtainedaccording to a similar manner to that of Preparation 69.

[0430] Preparation 70

[0431] Methyl 4-[5-(4-n-pentylphenyl)-1,3,4-thiadiazol-2-yl]- benzoate

[0432] IR (KBr) ; 2956, 2929, 2856, 1722, 1434, 1280, 1110 cmr¹ NMR(CDC1_(3,) 5) : 0.91 (3H, t, J=6.7Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m),2.68 (2H, t, J=7.7Hz), 3.96 (3H, s), 7.31 (2H, d, J=8.3Hz), 7.92 (2H, d,J=8.3Hz), 8.07 (2H, d, J=8.OHz), 8.16 (2H, d, J=8.OHz)

[0433] APCI-MASS : m/z =367 (M+H)⁺

[0434] Preparation 71

[0435] Methyl4-[5-[N-(tert-butoxycarbonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-yl]benzoate

[0436] IR (KBr) 2975, 1716, 1691, 1403, 1276, 1238, 1174, 1112 cm⁻¹ NMR(CDC1₃, 5) : 1.49 (9H, s), 1.7-1.9 (2H, m), 2.1-2.2 (2H, m), 2.8-3.0(2H, m), 3.3-3.5 (1H, m), 3.96 (3H, s), 4.22 (2H, d, J=13.3Hz), 8.01(2H, d, J=8.8Hz), 8.14 (2H, d, J=8.8Hz)

[0437] APCI-MASS : m/z =304 (M-Boc)⁺

[0438] Preparation 72

[0439] Methyl4-[5-[4-(3-phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoate

[0440] IR (KBr) : 2954, 1727, 1602, 1436, 1284, 1251, 1182 cm ⁻¹ NMR(CDC1₃, o) : 2.30 (2H, tt, J=6.1 and 6.1Hz), 3.96 (3H, s), 4.18 (2H, t,J=6.lHz), 4.25 (2H, t, J=6.lHz), 6.9-7.0 (3H, m), 7.02 (2H, d, J=8.8Hz),7.2-7.4 (2H, m), 7.95 (2H, d, J=8.5Hz), 8.06 (2H, d, J=8.6Hz), 8.15 (2H,d, J=8.6Hz)

[0441] APCI-MASS : m/z =447 (M+H)⁺

[0442] Preparation 73

[0443] Methyl 4-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoate

[0444] IR (KBr) 2952, 1710, 1606, 1517, 1432, 1278, 1251, 1180, 1110 cm⁻¹ NMR (CDC1_(3,) 5) : 3.88 (3H, s), 3.95 (3H, s), 6.98 (2H, d,J=8.8Hz), 7.94 (2H, d, J=8.8Hz), 8.07 (2H, d, J=8.6Hz), 8.13 (2H, d,J=8.6Hz)

[0445] APCI-MASS : m/z =327 (M+H)⁺

[0446] Preparation 74

[0447] Methyl 4-t5-(4-n-butoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoate

[0448] IR (KBr) : 2962, 2942, 2873, 1718, 1606, 1436, 1280, 1251, 1180cm−1 NMR (CDC1₃, 5) : 1.00 (3H, t, J=7.3Hz), 1.4-1.6 (2H, m), 1.7-1.9(2H, m), 3.95 (3H, s), 4.03 (2H, t, J=6.5Hz), 6.99 (2H, d, J=8.9Hz),7.94 (2H, d, J=8.9Hz), 8.06 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz)

[0449] APCI-MASS : m/z =369 (M+H)⁺

[0450] Preparation 75

[0451] Methyl 4-[5-(4-n-heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate

[0452] IR (KBr) : 2933, 2861, 1718, 1515, 1434, 1278, 1106 cm ¹ NMR(CDC1_(3,) 5) 0.90 (3H, t, J=6.5Hz), 1.3-1.6 (8H, m), 1.8-2.0 (2H, m),3.95 (3H, s), 4.03 (2H, t, J=6.5Hz), 6.99 (2H, d, J=8.8Hz), 7.94 (2H, d,J=8.8Hz), 8.06 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz)

[0453] APCI-MASS : m/z =411 (M+H)⁺

[0454] Preparation 76

[0455] Methyl 4-[5-(4-n-hexylphenyl)-l,3,4-thiadiazol-2-yl]-benzoate

[0456] IR (KBr) 2925, 2854, 1720, 1432, 1280, 1110 cm ⁻¹ NMR (CDC1₃, o): 0.89 (3H, t, J=6.6Hz), 1.3-1.7 (6H, m), 2.67 (2H, t, J=7.7Hz), 3.96(3H, s), 7.31 (2H, d, J=8.3Hz), 7.92 (2H, d, J=8.3Hz), 8.07 (2H, d,J-8.6Hz), 8.16 (2H, d, J=8.6Hz)

[0457] APCI-MASS : m/z =381 (M+H)⁺

[0458] Preparation 77

[0459] To a solution of 1-hydroxybenzotriazole (5.35 g) and4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (15 g)in the mixture of triethylamine (9.64 ml) and dichloromethane (450 ml)was added 1-ethyl-3-(3¹_ dimethylaminopropyl) carbodiimide hydrochloride(WSCDHCl) (12.6 g) and stirred for 4 hours at ambient temperature. Thereaction mixture was added to water. The organic layer was taken anddried over magnesium sulfate. Magnesium sulfate was filtered off, andthe filtrate was evaporated under reduced pressure to givel-[4-[4-(4-hexyloxyphenyl)piperazin- 1-yl]benzoyloxy]benzotriazole(16.78 g).

[0460] IR (KBr) : 1783.8, 1600.6, 1511.9, 1232.3, 1184.1 cm ⁻¹ NMR(CDC1₃ 5) : 0.91 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m),3.1-3.3 (4H, m), 3.5-3.7 (4H, m), 3.93 (2H, t, J=6.5Hz), 6.87 (2H, d,J=9.2Hz), 6.95 (2H, d, J=9.2Hz), 7.00 (2H, d, J=9.2Hz), 7.35- 7.6 (3H,m), 8.09 (lH, d, J=8.2Hz), 8.15 (2H, d, J=9.2Hz)

[0461] The following compounds [Preparations 78 to 97] were obtainedaccording to a similar manner to that of Preparation 77.

[0462] Preparation 78

[0463] 1-[4-[4-(trans-4-Cyclohexylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole

[0464] IR (KBr) : 2925.5, 1764.5, 1600.6, 1234.2 cm ⁻¹ NMR (CDC1₃, 0) :0.8-1.4 (12H, m), 1.5-2.1 (8H, m), 2.27 (lH, m), 2.6-2.8 (4H, m),3.4-3.6 (4H, m), 6.93 (2H, d, J=9.lHz), 7.3-7.6 (3H, m), 8.08 (lH, d,J=8.lHz), 8.11 (2H, d, J=9.lHz)

[0465] APCI-MASS : m/z 488 (M+H)⁺

[0466] Preparation 79

[0467] 1-[4-[4-(cis-4-Cyclohexylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole

[0468] IR (KBr) : 1762.6, 1600.6, 1232.3, 1186.0 cm ⁻¹ NMR (CDC1₃, o) :0.8-2.0 (20H, m), 2.26 (1H, m), 2.6-2.8 (4H, m), 3.4-3.6 (4H, m), 6.94(2H, d, J=9.OHz), 7.35-7.6 (3H, m), 8.08 (1H, d, J=8.lHz), 8.11 (2H, d,J=9.OHz)

[0469] APCI-MASS : m/z =488 (M+H)⁺

[0470] Preparation 80

[0471]1-[4-[4-(4-Cyclohexyloxyphenyl)piperazin-1-yl]-benzoyloxylbenzotriazole

[0472] Preparation 81

[0473]1-[4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzoyloxy]-benzotriazole

[0474] IR (KBr) : 1780.0, 1600.6, 1513.8, 1232.3, 1184.1 cm ¹ NMR(CDC1_(3,) 5) : 3.09 (4H, t, J-4.8Hz), 3.26 (4H, t, J=5.lHz), 3.62 (4H,t, J=5.lHz), 3.87 (4H, t, J=4.8Hz), 6.91 (2H, d, J=9.OHz), 7.00 (2H, d,J=9.OHz), 7.35-7.6 (3H, m), 8.09 (1H, d, J=7.lHz), 8.15 (2H, d, J=9.lHz)

[0475] Preparation 82

[0476]1-[4-[4-(4-Hexyloxyphenyl)-4-hydroxypiperidin-1-yl]-benzoyloxy]benzotriazole

[0477] IR (KBr) 3513.7, 1733.7, 1598.7, 1186.0 cm-1 NMR (CDC1_(3,) 5)0.91 (3H, t, J=6.5Hz), 1.2-2.05 (11H, m), 2.05-2.3 (2H, m), 3.4-3.6 (2H,m), 3.8-4.0 (2H, m), 3.96 (2H, t, J=6.5Hz), 6.90′(2H, d, J=8.8Hz), 7.00(2H, d, J=9.2Hz), 7.3-7.6 (5H, m), 8.07 (1H, d, J=8.2Hz), 8.12 (2H, d,J=9.2Hz)

[0478] APCI-MASS m/z =515 (M+H)⁺

[0479] Preparation 83

[0480]1-[4-[4-(4-Hexyloxyphenyl)piperidin-1-yl]benzoyloxy]-benzotriazole

[0481] IR (KBr) 2933.2, 1768.4, 1602.6, 1515.8, 1259.3, 1186.0 cm ⁻¹ NMR(CDCi₃l 5) : 0.90 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.7-2.1 (6H, m),2.65-2.9 (1H, m), 3.0-3.2 (2H, m), 3.94 (2H, t, J=6.5Hz), 4.05-4.2 (2H,m), 6.86 (2H, d, J=8.7Hz), 6.98 (2H d, J=9.lHz), 7.14 (2H, d, J=8.7Hz),7.35-7.6 (3H, m), 8.08 (1H, d, J=8.2Hz), 8.12 (2H, d, J=9.lHz)

[0482] Preparation 84

[0483] 1-[4-[4-(4-Pentyloxyphenyl)phenyl]benzoyloxy]-benzotriazole

[0484] Preparation 85

[0485]1-[4-[4-(3-Hexyloxyphenyl)piperazin-1-yl]benzoyloxy]-benzotriazole

[0486] IR (KBr) : 1774.2, 1602.6, 1236.1, 1187.9 cm ⁻¹ NMR (CDC1₃, 5) :0.91 (3H, t, J=6.6Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m), 3.3-3.5 (4H,m), 3.5-3.7 (4H, m), 3.96 (2H, t, J=6.5Hz), 6.47 (1H, d, J=8.OHz), 6.51(1H, s), 6.56 (1H, d, J=8.OHz), 6.98 (2H, d, J=9.OHz), 7.20 (1H, dd,J=8.0Hz), 7.3-7.6 (3H, m), 8.08 (1H, d, J=8.2Hz), 8.15 (2H, d, J=9.OHz)

[0487] Preparation 86

[0488]1-[4-4-(4-Hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl]benzoyloxy]benzotriazole

[0489] IR (KBr) : 1766.5, 1600.6, 1513.8, 1232.3, 1182.2 cm ⁻¹ NMR(CDC1_(3,) 5) : 0.91 (3H, t, J=6.5Hz), 1.2-1.6 (6H, m), 1.6-1.9 (2H, m),2.6-2.8 (2H, m), 3.75 (2H, t, J=5.7Hz), 3.97 (2H, t, J=6.5Hz), 4.05-4.2(2H, m), 6.0-6.15 (1H, mn), 6.89 (2H, d, J=8.8Hz), 6.96 (2H, d,J=9.lHz), 7.35 (2H, d, J=8.8Hz), 7.3-7.6 (3H, m), 8.08 (1H, d, J=8.2Hz),8.14 (2H, d, J=9.1Hz)

[0490] Preparation 87

[0491] 1-[4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]-benzoyloxy]benzotriazole

[0492] IR (KBr) : 1766.5, 1606, 1240, 1186.0, 918.0 cm ⁻¹ NMR (CDC1₃, 5): 1.0-2.5 (23H, m), 2.8-3.2 (4H, m), 3.9-4.1 (2H, m), 6.92 (2H, d,J=9.lHz), 7.3-7.6 (3H, m), 8.0-8.2 (3H, m)

[0493] APCI-MASS : m/z =488 (M+H)⁺

[0494] Preparation 88

[0495] 1-[4-[5-[2-(4-n-Hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole

[0496] IR (KBr) : 2942, 2865, 1785, 1513, 1240, 995 cm ⁻¹ NMR (CDC1_(3,)5) 0.90 (3H, t, J=6.6Hz), 1.2-1.5 (6H, m), 1.7-1.9 (2H, m), 3.14 (2H, t,J=7.6Hz), 3.50 (2H, t, J=7.6Hz), 3.94 (2H, t, J=6.5Hz), 6.85 (2H, d,J=8.6Hz), 7.15 (2H, d, J=8.6Hz), 7.4-7.6 (3H, m), 8.1-8.2 (1H, m), 8.16(2H, d, J=8.6Hz), 8.38 (2H, d, J=8.6Hz)

[0497] APCI-MASS : m/z =528 (M+H)⁺

[0498] Preparation 89

[0499] 1-[4-[5-(4-n-Pentylphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole

[0500] IR (KBr) : 2956, 2929, 2865, 1776, 1608, 1434, 1402, 1232 cm⁻¹NMR (CDC1₃, 5) : 0.91 (3H, t, J=6.6Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H,m), 2.70 (2H, t, J=7.7Hz), 7.34 (2H, d, J=8.3Hz), 7.4-7.6 (3H, m), 7.96(2H, d,

[0501] J=8.3Hz), 8.12 (1H, d, J=9.lHz), 8.26 (2H, d, J=8.7Hz), 8.41 (2H,d, J=8.7Hz) APCI-MASS : m/z =470 (M+H)⁺

[0502] Preparation 90

[0503]1-[4-[5-(4-n-Hexylphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxylbenzotriazole

[0504] IR (KBr) 2956, 2925, 2856, 1770, 1606, 1434, 1232, 1029 cm-1 NMR(CDC13, o) 0.90 (3H, t, J=6.6Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 2.69(2H, t, J=7.7Hz), 7.33 (2H, d, J=8.3Hz), 7.4-7.6 (3H, m), 7.95 (2H, d,J=8.3Hz), 8.12 (1H, d, J=8.lHz), 8.25 (2H, d, J=8.7Hz), 8.40 (2H, d,J=8.7Hz)

[0505] APCI-MASS :m/z 484 (M+H)⁺

[0506] Preparation 91

[0507]1-[4-[5-(4-n-Heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazoleIR (KBr) : 2925, 2856, 1770, 1602, 1440, 1263, 1222, 1029 cm-1 NMR(CDC1₃₁ b) : 0.91 (3H, t, J=6.5Hz), 1.2-1.6 (8H, m), 1.7-1.9 (2H, m),4.04 (2H, t, J=6.5Hz), 7.01 (2H, d, J=8.8Hz), 7.4-7.7 (3H, m), 7.97 (2H,d, J=8.8Hz), 8.12 (1H, d, J=8.2Hz), 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d,J=8.6Hz)

[0508] APCI-MASS :m/z =514 (M+H)⁺

[0509] Preparation 92

[0510]1-[4-[5-(4-n-Butoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole

[0511] IR (KBr) : 2956, 2873, 1774, 1602, 1442, 1251, 1180 cm ⁻¹ NMR(CDC1_(3,) 5) : 1.00 (3H, t, J=7.2Hz), 1.5-1.7 (2H, m), 1.7-1.9 (2H, m),4.06 (2H, t, J=6.7Hz), 7.02 (2H, d, J=8.7Hz), 7.4-7.6 (3H, m), 7.98 (2H,d, J=8.7Hz), 8.13 (1H, d, J=8.0Hz), 8.25 (2H, d, J=8.2Hz), 8.41 (2H, d,J=8.2Hz) APCI-MASS :m/z =472 (M+H)⁺

[0512] Preparation 93

[0513]1-[4-[5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazoleNMR (CDC13, 5) : 3.91 (3H, s), 7.04 (2H, d, J-8.9Hz), 7.2-7.5 (3H, m),8.00 (2H, d, J=8.9Hz), 8.13 (1H, d, J=8.lHz), 8.25 (2H, d, J=8.7Hz),8.42 (2H, d, J-8.7Hz)

[0514] Preparation 94

[0515]1-[4-[5-[4-(3-Phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole

[0516] IR (KBr) : 2927, 1778, 1603, 1438, 1240, 1178 cm ⁻¹ NMR(CDC1_(3,) 5) : 2.31 (2H, tt, J=6.0 and 6.0Hz), 4.19 (2H, t, J=6.OHz),4.27 (2H, t, J=6.OHz), 6.93 (2H, d, J=8.8Hz), 7.0-7.2 (3H, m), 7.2-7.6(SH, m), 7.98 (2H, d, J=8.8Hz), 8.13 (lH, d, J=8.3Hz), 8.25 (2H, d,J=8.3Hz), 8.41 (2H, d, J=8.3Hz)

[0517] APCI-MASS m/z =550 (M+H)⁺

[0518] Preparation 95

[0519] 1-[4-[5-(1-n-Octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole

[0520] IR (KBr) 3421, 2925, 2856, 1697, 1452, 1380, 1259, 1099 cm ⁻¹ NMR(CDC1_(3,) 5) : 0.89 (3H, t, J=6.8Hz), 1.2-1.7 (12H, m), 1.9-2.5 (10H,m), 3.0-3.2 (2H, m), 3.2-3.4 (1H, m), 7.4-7.6 (3H, m), 8.12 (1H, d,J=8.lHz), 8.20 (2H, d, J=8.6Hz), 8.39 (2H, d, J=8.6Hz) APCI-MASS m/z=519 (M+H)⁺

[0521] Preparation 96

[0522]1-[4-[5-(4-n-Pentyloxyphenyl)thiophen-2-yl]benzoyloxy]-benzotriazole

[0523] IR (KBr) 2865, 1772, 1691, 1600, 1540, 1513, 1454, 1251, 1180 cm⁻¹ NMR (CDC1₃, 5) : 0.95 (3H, t, J=7.2Hz), 1.3-1.6 (4H, m), 1.7-2.0 (2H,m), 4.00 (2H, t, J=6.4Hz), 6.94 (2H, d, J=8.4Hz), 7.25 (lH, d, J=3.5Hz),7.4-7.7 (6H, m), 7.81 (2H, d, J=8.lHz), 8.11 (1H, d, J=8.4Hz), 8.27 (2H,d, J=8.lHz) APCI-MASS : m/z =484 (M+H)⁺

[0524] Preparation 97

[0525] 1-[4-[5-(4-n-Pentyloxyphenyl)furan-2-yllbenzoyloxy]-benzotriazole

[0526] IR (KBr) 2948, 2865, 1778, 1600, 1502, 1479, 1253 cm ¹ NMR(CDC1₃₁ 5) : 0.95 (3H, t, J=7.2Hz), 1.3-1.6 (4H, m), 1.7-1.9 (2H, m),4.01 (2H, t, J=6.5Hz), 6.68 (1H, d, J=3.6Hz), 6.9-7.1 (3H, m), 7.4-7.6(3H, m), 7.71 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.7Hz), 8.11 (1H, d,J=8.2Hz), 8.28 (2H, d, J=8.7Hz) APCI-MASS : m/z =468 (M+H)⁺

[0527] Preparation 98

[0528] To a solution of 4-n-pentyloxybenzoic acid benzotriazole-1-ylester (20 g) in N,N-dimethylformamide (100 ml) was addedthiosemicarbazide (6.73 g) and stirred for 7 hours at ambienttemperature. The reaction mixture was pulverized with diisopropyl ether.The precipitate was collected by filtration to give1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g).

[0529] IR (KBr) : 3419.2, 3151.1, 1691.3, 1259.3 cm ⁻¹ NMR (DMSO-d₆, o)0.90 (3H, t, J=7.OHz), 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 4.02 (2H, t,J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.58 (2H, s), 9.28 (1H, s), 10.22 (1H,s)

[0530] APCI-MASS m/z =282 (M+H)⁺

[0531] Preparation 99

[0532] To a slurry of 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20g) in toluene (213.3 ml) at 40° C, was added dropwise over 30 minutes,methanesulfonic acid (6.92 ml). The mixture was refluxed for 12 hours.After cooling to 10° C, the resulting precipitate was filtered anddried. The precipitate was dissolved in water, the solution was adjustedto pH 9 with 1N sodium hydroxide and extracted with ethyl acetate. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure to give2-amino-5-(4-n-pentyloxyphenyl)-1,3,4-thiadiazole (4.314 g).

[0533] IR (KBr) : 3261.0, 3174.3, 1608.3, 1255.4 cm ¹ NMR (CDC1₃, o) :0.94 (3H, t, J=7.0Hz), 1.2-1.6 (4H, m), 1.6-1.9 (2H, m), 3.99 (2H, t,J=6.5Hz), 5.53 (2H, s), 6.92 (2H, d, J=8.8Hz), 7.70 (2H, d, J=8.8Hz)

[0534] APCI-MASS : m/z =264 (M+H)⁺

[0535] Preparation 100

[0536] To a suspension of2-amino-5-(4-n-pentyloxyphenyl)-1,3,4-thiadiazole (4.314 g) in ethanol(43 ml) was added ethyl 4-bromoacetylbenzoate (4.21 g) and refluxed for4 hours. The reaction mixture was pulverized with ethyl acetate. Theprecipitate was filtered and dried. To a suspension of the powder inxylene (40 ml) was added trifluoroacetic acid (10 ml) and refluxed for 3hours. The reaction mixture was pulverized with diisopropyl ether. Theprecipitate was filtered and dried to give 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl estertrifluoroacetic acid salt (5.3 g).

[0537] IR (KBr) : 1710.6, 1610.3, 1272.8 cm ⁻¹ APCI-MASS : m/z =436(M+H)⁺

[0538] Preparation 101

[0539] To a solution of4-[2-(4-pentyloxyphenyl)imidazo-[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester trifluoroacetic acid salt (5.2 g) in the mixture ofmethanol (104 ml) and tetrahydrofuran (52 ml) was added 2N NaOH aq. (47ml) and refluxed for 36 hours. The reaction mixture was adjusted to pH1-2 with IN HCl and the resulting precipitate was collected byfiltration to give 4-[2-(4-pentyloxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.27 g).

[0540] IR (KBr) 1681.6, 1606.4, 1255.4, 1174.4 cm ⁻¹ APCI-MASS : m/z=408 (M+H)⁺

[0541] Preparation 102

[0542] To a solution of 1-hydroxybenzotriazole (1.67 g) and4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]- benzoicacid (4.2 g) in dichloromethane (170 ml) was added1-ethyl-3-(31-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HCl)(2.95 g) and stirred for 6 hours at ambient temperature. The reactionmixture was added to water. The organic layer was taken and dried overmagnesium sulfate. Magnesium sulfate was filtered off, and the filtratewas evaporated under reduced pressure to give 1-[4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoyloxylbenzotriazole (2.456 g).

[0543] IR (KBr) : 1772.3, 1604.5, 1251.6, 983.5 cm ⁻¹ NMR (CDC1₃, 5) :0.96 (3H, t, J=7.OHz), 1.2-1.6 (4H, m), 1.6-1.9 (2H, m), 4.05 (2H, t,J=6.5Hz), 7.01 (2H, d, J=8.3Hz), 7.4-7.6 (3H, m), 7.83 (2H, d, J=8.3Hz),8.07 (2H, d, J=8.OHz), 8.10 (lH, d, J=8.2Hz), 8.21 (lH, s), 8.33 (2H, d,J=8.OHz)

[0544] APCI-MASS m/z =525 (M+H)⁺

[0545] The following compound was obtained according to a similar mannerto that of Preparation 98.

[0546] Preparation 103

[0547] 1-[4-(4-Ethoxyphenyl)benzoyl]-3-thiosemicarbazide IR (KBr) :3295.7, 3263.0, 1668.1, 1257.4 cm ⁻¹ NMR (DMSO-d₆i o) : 1.35 (3H, t,J=7.OHz), 4.08 (2H, q, J=7.OHz), 7.03 (2H, d, J=8.8Hz), 7.68 (2H, d,J=8.8Hz), 7.6-8.1 (6H, m), 9.35 (1H, s), 10.40 (1H, s)

[0548] APCI-MASS m/z =316 (M+H)⁺

[0549] The following compounds [Preparations 104 and 105] were obtainedaccording to a similar manner to that of Preparation 99.

[0550] Preparation 104

[0551] 2-Amino-5-[4-(4-ethoxyphenyl)phenyl]-1,3,4-thiadiazole

[0552] IR (KBr) : 3432.7, 1602.6, 1500.3, 825.4 cm ⁻¹

[0553] Preparation 105

[0554] 2-Amino-5-(4-phenylphenyl)-1,3,4-thiadiazole

[0555] IR (KBr) : 3278.4, 3085.5, 1643.1, 1513.8 cm~¹

[0556] APCI-MASS m/z 254 (M+H)⁺

[0557] The following compounds [Preparations 106 and 107] were obtainedaccording to a similar manner to that of Preparation 100.

[0558] Preparation 106

[0559] 4-[2-[4-(4-Ethoxyphenyl)phenyllimidazo[2,1-b][1,3,4]-thiadiazol-6-yllbenzoic acid ethyl ester trifluoroacetic acid salt

[0560] IR (KBr) 1708.6, 1604.5, 1274.7, 1105.0, 819.6, 729.0 cm⁻¹

[0561] APCI-MASS m/z =470 (M+H)⁺

[0562] Preparation 107

[0563] 4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt

[0564] IR (KBr) : 1710.6, 1606.4, 1278.6, 1106.9 cm ⁻¹

[0565] APCI-MASS : m/z =426 (M+H)⁺

[0566] The following compounds [Preparations 108 to 110] were obtainedaccording to a similar manner to that of Preparation 101.

[0567] Preparation 108

[0568] 4-[2-[4-(4-Ethoxyphenyl)phenyl]imidazo[2,1-b][1,3,4]-thiadiazol-6-yl]benzoic acid

[0569] IR (KBr) 1683.6, 1604.5, 1278.6, 1253.5, 821.5, 727.0 cm⁻¹

[0570] Preparation 109

[0571] 4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid

[0572] IR (KBr) : 1706.7, 1608.3, 1276.6, 1251.6 cm ¹

[0573] APCI-MASS : m/z =398 (M+H)⁺

[0574] Preparation 110

[0575] 4-[4-(4-n-Pentylcyclohexyl)piperazin-1-yl]benzoic acidmonohydrochloride

[0576] IR (KBr) 2923.6, 2854.1, 1693.2, 1610.3 cm ⁻¹

[0577] APCI-MASS : m/z =359 (M+H)⁺

[0578] The following compounds [Preparations 111 and 1121 were obtainedaccording to a similar manner to that of Preparation 102.

[0579] Preparation 111

[0580]1-[4-[2-[4-(4-Ethoxyphenyl)phenyl]imidazo[2,1-b][1,3,41-thiadiazol-6-yl]benzoyloxy]benzotriazole IR (KBr) : 1778.0, 1714.4, 1602.6,1276.6, 1255.4, 821.5, 779.1 cm ⁻¹

[0581] APCI-MASS : m/z =559 (M+HI)⁺

[0582] Preparation 112

[0583]1-[4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoyloxy]benzotriazole

[0584] IR (KBr) 1778.0, 1714.4, 1606.4, 1278.6, 1251.6, 821.5, 723.2cm−1

[0585] APCI-MASS : m/z =515 (M+H)⁺

[0586] Preparation 113

[0587] To a solution of 4-phenylbenzoic acid (10.Og),1-hydroxybenzotriazole (7.5 g) and thiosemicarbazide (5.1 g) indimethylformamide (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (14.45 g) and stirred for 12 hours at ambienttemperature. The reaction mixture was pulverized with water. Theprecipitate was collected by filtration and dried under reduced pressureto give 1-(4-phenylbenzoyl)-3-thiosemicarbazide (10.274 g).

[0588] IR (KBr) : 3369.0, 3185.8, 1656.6, 1610.3, 1261.2, 744.4 cm ⁻¹

[0589] APCI-MASS : m/z =272 (M+H)⁺

[0590] The following compounds [Preparations 114 and 115] were obtainedaccording to a similar manner to that of Preparation 77.

[0591] Preparation 114

[0592]1-[4-[4-(4-n-Pentylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole

[0593] IR (KBr) 2919.7, 2848.3, 1778.0, 1600.6, 1232.3 cm ⁻¹ NMR (CDCl₃,5) : 0.89 (3H, t, J=6.6Hz), 0.8-1.1 (2H, m), 1.1-2.0 (15H, m), 2.6-2.8(4H, m), 3.4-3.6 (4H, m), 6.93 (2H, d, J=9.2Hz), 7.4-7.6 (3H, m),8.0-8.2 (3H, m)

[0594] APCI-MASS : m/z =476 (M+H)⁺

[0595] Preparation 115

[0596]1-[4-[2-[4-(4-Cyclohexylphenyl)piperazin-1-yl]ethyl]-benzoyloxy]benzotriazole

[0597] IR (KBr) 2923.6, 1799.3, 1781.9, 1608.3, 1232.3, 979.7 cm^(−1 NMR (CDCl) ₃, 5) : 1.1-1.6 (6H, m), 1.6-2.1 (4H, m), 2.43 (1H, m),2.6-2.8 (6H, m), 2.9-3.1 (2H, m), 3.2-3.4 (4H, m), 6.88 (2H, d,J=8.6Hz), 7.12 (2H, d, J=8.6Hz), 7.46 (2H, d, J=8.3Hz), 7.4-7.7 (3H, m),8.11 (1H, dd, J=1.4 and 7.7Hz), 8.21 (2H, d, J=8.3Hz)

[0598] APCI-MASS m/z =510 (M+H)⁺

[0599] Preparation 116

[0600] To a suspension of 1-(4-cyclohexylphenyl)piperazinedihydrobromide (2.5 g) and potassium bicarbonate (2.125 g) inN,N-dimethylformamide (6 ml) was added methyl 4-(2-chloroethylphenyl)benzoate (1.22 g) and stirred for 24 hours at 120° C. The reactionmixture was added to a mixture of water and ethyl acetate. The organiclayer was taken and dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was evaporated under reduced pressureto give methyl 4-[2-[4-(4-cyclohexylphenyl)-piperazin-1-yllethyl]benzoate (1.247 g).

[0601] IR (KBr) : 2927.4, 2852.2 1724.0, 1652.7, 1278.6 cm ⁻¹ NMR(CDCl₃, 5) : 1.2-1.5 (5H, m), 1.7-2.0 (5H, m), 2.42 (1H, m), 2.6-2.8(6H, m), 2.8-3.0 (2H, m), 3.1-3.3 (4H, m), 3.91 (3H, s), 6.87 (2H, d,J=8.7Hz), 7.11 (2H, d, J=8.7Hz), 7.29 (2H, d, J=8.3Hz), 7.96 (2H, d,J=8.3Hz)

[0602] APCI-MASS : m/z =407 (M+H)⁺

[0603] The following compound was obtained according to a similar mannerto that of Preparation 43.

[0604] Preparation 117

[0605] 4-[2-[4-(4-Cyclohexylphenyl)piperazin-1-yl]ethyl]benzoic acid

[0606] IR (KBr) 3673.7, 3648.7, 1710.6, 1515.8, 1243.9, 1228.4 cm ⁻¹

[0607] APCI-MASS m/z =393 (M+H)⁺

[0608] Preparation 118

[0609] To a solution of 4-(4′-hydroxyphenyl)benzoic acid (15.00 g) indimethylformamide (150 ml) were added successively n-propyl bromide(14.63 ml) and potassium carbonate (24.19 g). The mixture was stirred at60° C for 24 hours, during this period additional n-propyl bromide (1.27ml) and potassium carbonate (1.94 g) were added into the mixture. Aftercooling to room temperature, the reaction mixture was poured into water(600 ml) and then the mixture was stirred for 30 minutes at roomtemperature. The resulting precipitate was filtered, washed with water,and dried to give the objective compound, propyl4-(41-propoxyphenyl)benzoate (20.48 g), as a white solid.

[0610] IR (KBr) : 2966, 1711, 1605 cm⁻NMR (CDC1₃, 5) 1.06 (6H, m), 1.83(4H, m), 3.97 (2H, t, J=6.6Hz), 4.30 (2H, t, J=6.6Hz), 6.98 (2H, m),7.59 (4H, m), 8.08 (2H, m)

[0611] APCI-MASS m/z =299 (M+H)⁺

[0612] Preparation 119

[0613] To a mixture of propyl 4-(41-propoxyphenyl)benzoate (20.00 g) ina mixture of ethanol (100 ml) and tetrahydrofuran (40 ml) was addedhydrazine monohydrate (32.5 ml). The mixture was refluxed for 2 hours,during this period additional hydrazine monohydrate (32.5 ml) was addedinto the mixture. After cooling to room temperature, the reactionmixture was poured into water (1800 ml) and then the mixture was stirredfor 30 minutes at room temperature. The resulting precipitate wasfiltered, washed with water, and dried to give the objective compound,4-(4′-propoxyphenyl)-benzoyl hydrazine (17.63 g), as a white solid.

[0614] IR (KBr) : 3338, 3277, 3194, 2966, 2929, 1612 cm ⁻¹ NMR (DMSO-d₆l5) : 0.99 (3H, t, J=7.4Hz), 1.75 (2H, m), 3.98 (2H, t, J=6.5Hz), 4.50(2H, s), 7.03 (2H, d, J=8.8Hz), 7.68 (4H, m), 7.89 (2H, d, J=8.4Hz),9.79 (1H, s)

[0615] APCI-MASS : m/z =271 (M+H)⁺

[0616] The Starting Compound in the following Examples 1 to 30 and TheObject Compounds (1) to (30) in the following Examples 1 to 30 areillustrated by chemical formulae as below.

[0617] The Starting Compound (the same in Examples 1 to 30)

[0618] In the following Examples, The Object Compound (X) [e.g. TheObject Compound (1)] means the object compound of Example (X) [e.g.Example (1)]. Example No. R¹  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Example 1

[0619] To a solution of The Starting Compound (33.55 g) and1-[4-hexyloxyphenyl)piperazin-1-yllbenzoyloxy]- benzotriazole (17.48 g)in dimethylformamide (335.5 ml) was added diisopropylethylamine (7.32ml) and stirred for 8 hours at ambient temperature. The reaction mixturewas pulverized with ethyl acetate. The precipitate was collected byfiltration and dried under reduced pressure. The powder was added towater and subjected to ion-exchange column chromatography on DOWEX-50WX4(Trademark : prepared by Dow Chemical) and eluted with water. Thefractions containing The Object Compound were combined and subjected tocolumn chromatography on ODS (YMC-gel ODS-AM-S-50) (Trademark : preparedby Yamamura Chemical Lab.) and eluted with 25% acetonitrile aq. Thefractions containing The Object Compound were combined and evaporatedunder reduced pressure to remove acetonitrile. The residue waslyophilized to give The Object Compound (1) (27.86 g).

[0620] The Object Compounds (2) to (21) were obtained according to asimilar manner to that of Example 1.

Example 2

[0621] IR (KBr) 3350, 1666.2, 1629.6, 1238.1 cm ⁻¹ NMR (DMSO-d₆, 5) :0.96 (3H, d, J=6.7Hz), 0.8-1.5 (15H, m), 1.5-2.1 (12H, m), 2.1-2.65 (4H,m), 3.0-3.2 (SH, m), 3.1-3.55 (4H, m), 3.65-4.5 (14H, m), 4.6- 5.5 (1lH,m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, s), 6.83 (lH, d, J=8.2Hz), 6.99(2H, d, J=8.6Hz), 7.04 (1H, s), 7.25-7.5 (3H, m), 7.81 (2H, d, J=8.6Hz),8.09 (lH, d, J=8.7Hz), 8.28 (lH, d, J=8.7Hz), 8.45 (1H, d, J=6.7Hz),8.83 (lH, s) FAB-MASS : m/z =1231 (M-SO₃+Na)+

Example 3

[0622] IR (KBr) : 3359.4, 1666.2, 1629.6, 1511.9 cm ⁻¹ NMR (DMSO-d₆, 6): 0.96 (3H, d, J=6.7Hz), 0.7-2.1 (27H, m), 2.1-2.7 (4H, m), 3.0-3.4 (9H,m), 3.6-4.5 (14H, m), 4.6-5.5 (11H, m), 6.72 (lH, d, J=8.2Hz), 6.81 (1H,s), 6.83 (lH, d, J=8.2Hz), 6.99 (2H, d, J=8.6Hz), 7.04 (lH, s), 7.2-7.5(3H, m), 7.81 (2H, d, J=8.6Hz), 8.09 (lH, d, J=8.7Hz), 8.28 (lH, d,J=8.7Hz), 8.45 (1H, d, J=6.7Hz), 8.83 (1H, s) FAB-MASS : m/z =1231(M-S0₃+Na)+

Example 4

[0623] IR (KBr) : 3353.6, 1668.1, 1629.6, 1508.1, 1234.2 cm ⁻¹ NMR(DMSO-d₆l 5) : 0.96 (3H, d, J=7.OHz), 1.05 (3H, d, J=6.OHz), 0.8-2.6(17H, m), 3.0-4.5 (23H, m), 4.5- 5.3 (1OH, m), 5.45 (lH, d, J=4.8Hz),6.6-7.2 (10H, m), 7.2-7.5 (3H, m), 8.06 (2H, d, J=8.9Hz), 8.25 (1H, d,J=8.OHz), 8.40 (1H, d, J=8Hz), 8.61 (1H, d, J=6.7Hz), 8.82 (1H, s)

[0624] FAB-MASS : m/z =1343 (M+Na)+

[0625] Analysis Calcd. for C₅₈H₇₇N₁₀O₂₂SNa·8H₂O

[0626] C 47.54, H 6.40, N 9.56

[0627] Found : C 47.65, H 6.36, N 9.42

Example 5

[0628] IR (KBr) 3355.5, 1668.1, 1629.6, 1511.9, 1234.2 cm ⁻¹ NMR(DMSO-d₆, 5) : 0.96 (3H, d, J=6.8Hz), 1.07 (3H, d, J=5.7Hz), 1.7-2.1(3H, m), 2.1-2.7 (4H, m), 2.99 (4H, t, J=4.7Hz), 3.1-3.3 (5H, m),3.35-3.5 (4H, m), 3.6-3.8 (2H, m), 3.72 (4H, t, J=4.7Hz), 3.8-4.5 (12H,m), 4.65-5.05 (7H, m), 5.07 (1H, d, J=5.6Hz), 5.13 (1H, d, J=3.2Hz),5.21 (1H, d, J=4.6Hz), 5.45 (1H, d, J=6.OHz), 6.73 (1H, d, J=8.2Hz),6.81 (1H, s), 6.83 (lH, dd, J=1.9 and 8.2Hz), 6.87 (2H, d, J=9.4Hz),6.93 (2H, d, J=9.4Hz), 7.00 (2H, d, J=9.0Hz), 7.04 (1H, d, J=1.9Hz),7.2-7.5 (3H, m), 7.81 (2H, d, J=9.OHz), 8.04 (1H, d, J=9.OHz), 8.21 (1H,d, J=8.4Hz), 8.39 (1H, d, J=7.lHz), 8.83 (1H, s)

[0629] FAB-MASS m/z =1330 (M+Na)⁺

[0630] Analysis Calcd. for C₅₆H₇₄N₁₁0₂₂SNa,6H₂O:

[0631] C 47.49, H 6.12, N 10.88

[0632] Found : C 47.26, H 6.07, N 10.73

Example 6

[0633] IR (KBr) 3349, 1668.1, 1627.6, 1247.7 cm⁻¹ NMR (DMSO-d₆, 5) :0.87 (3H, t, J=6.6Hz), 0.96 (3H, d, J=6.8Hz), 1.06 (3H, d, J=5.8Hz),1.2-1.5 (6H, m), 1.6-2.7 (13H, m), 3.1-3.4 (3H, m), 3.6-4.5 (18H, m),3.7-5.1 (8H, m), 5.11 (lH, d, J=5.6Hz), 5.14 (1H, d, J=3.lHz), 5.22 (1H,d, J=4.6Hz), 5.45 (lH, d, J=6.OHz), 6.73 (lH, d, J=8.3Hz), 6.81 (1H, s),6.83 (1H, d, J=8.3Hz), 6.85 (2H, d, J=8.8Hz), 6.98 (2H, d, J=8.9Hz),7.04 (1H, s), 7.2-7.5 (5H, m), 7.78 (2H, d, J=8.8Hz), 8.06 (1H, d,J=9.3Hz), 8.24 (1H, d, J=8.lHz), 8.37 (1H, d, J=7.5Hz), 8.83 (1H, s)

[0634] FAB-MASS : m/z =1360 (M+Na)⁺

[0635] Analysis Calcd. for C₅₉H₈₀N₉O₂₃SNa-6H₂O:

[0636] C 48.99, H 6.41, N 8.71

[0637] Found : C 48.78, H 6.28, N 8.59

Example 7

[0638] IR (KBr) : 3384.5, 1666.2, 1627.6, 1510.0, 1047.2 cm ¹ NMR(DMSO-d₆, 5) 0.88 (3H, t, J=6.6Hz), 0.96 (3H, d, J=6.8Hz), 1.31 (3H, d,J=6.4Hz), 1.2-1.5 (6H, m), 1.5-2.1 (9H, m), 2.1-2.45 (3H, m), 2.5-3.0(4H, m), 3.1-3.35 (1H, m), 3.6-4.5 (18H, m), 4.7-5.3 (7H, m), 5.08 (1H,d, J=5.6Hz), 5.14 (1H, d, J=3.2Hz), 5.22 (1H, d, J=4.5Hz), 5.45 (1H, d,J=6.0Hz), 6.73 (1H, d, J=8.2Hz), 6.8-6.9 (4H, m), 6.97 (2H, d, J=9.OHz),7.04 (1H, s), 7.15 (2H, d, J=8.7Hz), 7.2- 7.5 (3H, m), 7.79 (2H, d,J=8.7Hz), 8.04 (1H, d, J=9.OHz), 8.22 (1H, d, J=8.4Hz), 8.36 (1H, d,J=7.lHz), 8.84 (1H, s)

[0639] FAB-MASS : m/z =1353 (M+Na)⁺

[0640] Analysis Calcd. for C₅₉H₈₀N₉O₂₂SNa,5H₂O:

[0641] C 50.17, H 6.42, N 8.92

[0642] Found : C 50.09, H 6.36, N 8.88

Example 8

[0643] IR (KBr) 3334.3, 1668.1, 1631.5, 1521.6, 1247.7 cm ⁻¹ NMR(DMSO-d₆, 5) : 0.91 (3H, t, J=7.2Hz), 0.96 (3H, d, J=7.3Hz), 1.09 (3H,d, J=5.8Hz), 1.2-1.5 (4H, m), 1.65-2.1 (5H, m), 2.1-2.7 (4H, m), 3.1-3.3(1H, m), 3.6-4.6 (16H, m), 4.7-5.3 (7H, m), 5.11 (1H, d, J=5.5Hz), 5.17(1H, d, J=3.lHz), 5.26 (1H, d, J=4.5Hz), 5.54 (1H, d, J=5.9Hz), 6.73(1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.85 (1H, s), 7.04 (2H, d,J-8.5Hz), 7.06 (1H, s), 7.2-7.5 (3H, m), 7.6-7.9 (8H, m), 8.01 (2H, d,J=8.4Hz), 8.1 (1H, d, J=9.OHz), 8.3 (1H, d, J=8.4Hz), 8.8 (1H, d,J=7.lHz), 8.85 (1H, s)

[0644] FAB-MASS : m/z =1323 (M+Na)+

[0645] Analysis Calcd. for C₅₉H₇₃N₈0₂₂SNa-5H₂O:

[0646] C 50.93, H 6.01, N 8.05

[0647] Found : C 51.14, H 6.13, N 8.03

Example 9

[0648] IR (KBr) 3349.7, 1668.1, 1629.6, 1236.1 cm¹ NMR (DMSO-d₆, 5) :0.91 (3H, t, J=6.3Hz), 0.96 (3H, d, J=6.8Hz), 1.06 (3H, d, J=5.8Hz),1.2-1.5 (6H, m), 1.5-2.1 (SH, m), 2.1-2.7 (4H, m), 3.1-3.5 (9E, m),3.6-4.5 (16H, m), 4.7-5.3 (7H, m), 5.07 (1H, d, J=5.6Hz), 5.14 (1H, d,J=3.2Hz), 5.22 (lH, d, J=4.5Hz), 5.45 (1H, d, J=5.9Hz), 6.38 (1H, d,J=8.OHz), 6.49 (1H, s), 6.56 (1H, d, J=8.OHz), 6.72 (1H, d, J=8.2Hz),6.80 (1H, s), 6.82 (1H, d, J=8.2Hz), 7.00 (2H, d, J=9.OHz), 7.04 (1H,s), 7.12 (1H, dd, J=8.OHz), 7.2-7.5 (3H, m), 7.81 (2H, d, J=9.OHz), 8.08(1H, d, J=9.OHz), 8.25 (1H, d, J=8.4Hz), 8.39 (1H, d, J=7.lHz), 8.83(1H, S)

[0649] FAB-MASS : m/z =1345 (M+Na)+

[0650] Analysis Calcd. for C₅₈H₇₉N,₀0₂₂SNa,5H₂O:

[0651] C 49.29, H 6.35, N 9.91

[0652] Found C 49.12, H 6.11, N 9.81

Example 10

[0653] IR (KBr) : 3332.4, 1664.3, 1627.6, 1510.0, 1234.2 cm ⁻¹ NMR(DMSO-d₆, 5) : 0.91 (3H, t, J=6.6Hz), 0.96 (3H, d, J=6.7Hz), 1.07 (3H,d, J=5.9Hz), 1.2-1.5 (6H, m), 1.6-2.1 (5H, m), 2.1-2.7 (6H, m), 3.1-3.3(1H, m), 3.5-4.5 (20H, m), 4.65-5.2 (9H, m), 5.22 (1H, d, J=4.4Hz), 5.46(1H, d, J=6Hz), 6.18 (1H, m), 6.73 (1H, d, J=8.2Hz), 6.81 (1H, s), 6.83(1H, d, J=8.2Hz), 6.90 (2H, d, J=8.9Hz), 6.97 (2H, d, J=9.lHz), 7.04(1H, s), 7.2-7.5 (3H, m), 7.40 (2H, d, J=8.9Hz), 7.81 (2H, d, J=9.lHz),8.03 (1H, d, J=9.OHz), 8.21 (1H, d, J=8.4Hz), 8.36 (1H, d, J=7.lHz),8.83 (1H, s)

[0654] FAB-MASS : m/z =1342 (M+Na)⁺

[0655] Analysis Calcd. for C₅₉H₇₈N₉ ₂₂SNa,7H₂O:

[0656] C 48.99, H 6.41, N 8.71

[0657] Found : C 48.65, H 6.03, N 8.64

Example 11

[0658] IR (KBr) : 3380, 1664.3, 1631.5, 1243.9 cm ¹ NMR (DMSO-d₆, 5)0.92 (3H, d, J=8.3Hz), 1.06 (3H, d, J=5.7Hz), 1.0-2.1 (32H, m), 2.1-3.0(8H, m), 3.1- 3.3 (1H, m), 3.6-4.5 (16H, m), 4.65-5.2 (7H, m), 5.07 (1H,d, J=5.6Hz), 5.14 (1H, d, J=3.lHz), 5.22 (1H, d, J=4.5Hz), 5.43 (1H, d,J=6.OHz), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, s), 6.83 (1H, d, J=8.2Hz),6.92 (2H, d, J=8.8Hz), 7.04 (1H, s), 7.25-7.5 (3H, m), 7.76 (2H, d,J=8.8Hz), 8.06 (1H, d, J=8.2Hz), 8.25 (1H, d, J=8.6Hz), 8.35 (1H, d,J=8.2Hz), 8.83 (1H, s)

[0659] FAB-MASS : m/z =1311 (M+Na)⁺

[0660] Analysis Calcd. for C₅₈H₈₄N₁₀0₂₁S,8H₂O:

[0661] C 48.60, H 7.03, N 9.77

[0662] Found : C 48.58, H 6.57, N 9.69

Example 12

[0663] IR (KBr) : 3357, 2933, 1631, 1535, 1515, 1442, 1280, 1047 cm ⁻¹NMR (DMSO-d₆, 5) : 0.88 (3H, t, J=6.7Hz), 0.97 (3H, d, J=6.8Hz), 1.10(3H, d, J=5.9Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m), 1.7-2.1 (3H, m),2.1-2.4 (3H, m), 3.5-3.6 (1H, m), 2.67 (2H, t, J=7.7Hz), 3.1-3.3 (1H,m), 3.7-4.6 (14H, m), 4.8-5.1 (7H, m), 5.09 (1H, d, J=5.4Hz), 5.16 (1H,d, J=3.lHz), 5.24 (1H, d, J=4.6Hz), 5.53 (1H, d, J=5.9Hz), 6.73 (1H, d,J=8.2Hz), 6.8-7.0 (2H, m), 7.04 (1H, s), 7.22 (1H, br s), 7.3-7.5 (4H,m), 7.95 (2H, d, J=8.2Hz), 8.0- 8.2 (5H, m), 8.21 (1H, d, J=7.7Hz), 8.83(1H, s), 8.90 (1H, d, J=7.OHz)

[0664] FAB-MASS : m/z =1315.1 (M+Na)⁺

[0665] Analysis Calcd. for C₅₅H₆₉N₁₀O₂₁NaS,6H₂O:

[0666] C 47.14, H 5.83, N 9.99

[0667] Found : C 47.39, H 5.69, N 10.05

Example 13

[0668] IR (KBr) 3438, 3357, 2931, 1631, 1537, 1515, 1442, 1280, 1047 cm⁻¹ NMR (DMSO-d₆, 5) : 0.87 (3H, t, J=6.7Hz), 0.97 (3H, d, J=6.8Hz), 1.09(3H, d, J=6.OHz), 1.2-1.4 (6H, m), 1.5-1.7 (2H, m), 1.8-2.1 (2H, in),2.2-2.4 (3H, m), 2.5-2.6 (1H, m), 2.67 (2H, t, J=7.7Hz), 3.1-3.3 (1H,m), 3.4-4.5 (14H, m), 4.7-5.1 (7H, m), 5.08 (1H, d, J=5.SHz), 5.17 (1H,d, J=3.2Hz), 5.23 (1H, d, J=4.6Hz), 5.53 (lH, d, J=5.8Hz), 6.73 (1H, d,J=8.2Hz), 6.8-7.0 (2H, m), 7.04 (lH, s), 7.2-7.5 (5H, m), 7.95 (2H, d,J=8.2Hz), 8.0-8.3 (6H, m), 8.84 (1H, s), 8.89 (1H, d, J=7.OHz)

[0669] APCI-MASS : m/z =1328.9 (M+Na)⁺

[0670] Analysis Calcd. for C₅₆H₇₁N₁₀O₂₁S₂Na.7H₂O:

[0671] C 46.92, H 5.98, N 9.77

[0672] Found : C 47.07, H 5.52, N 9.76

Example 14

[0673] IR (KBr) 3386, 2935, 2858, 1666, 1631, 1515, 1442, 1257, 1047 cm⁻¹ NMR (DMSO-d₆, 5) : 0.88 (3H, t, J=6.7Hz), 0.97 (3H, d, J=6.7Hz), 1.09(3H, d, J=5.9Hz), 1.2-1.5 (8H, m), 1.7-2.1 (5H, m), 2.2-2.5 (3H, m),2.5-2.6 (1H, m), 3.1-3.3 (1H, m), 3.7-4.5 (16H, m), 4.7-5.1 (7H, m),5.11 (1H, d, J=5.5Hz), 5.18 (lH, d, J=3.lHz), 5.26 (1H, d, J=4.6Hz),5.54 (1H, d, J=5.8Hz), 6.73 (1H, d, J=8.2Hz), 6.8-7.0 (2H, m), 7.05 (1H,s), 7.13 (2H, d, J=8.8Hz), 7.2-7.5 (3H, m), 7.97 (2H, d, J=8.8Hz),8.0-8.2 (5H, m), 8.24 (1H, d, J=7.7Hz), 8.85 (1H, s), 8.92 (1H, d,J=7.OHz)

[0674] FAB-MASS m/z =1359 (M+Na)⁺

[0675] Analysis Calcd. for C₅₇H₇₃N₁₀O₂₂S₂Na-7H₂O:

[0676] C 46.78, H 5.99, N 9.57

[0677] Found C 46.90, H 6.24, N 9.56

Example 15

[0678] IR (KBr) : 3350, 2956, 1633, 1517, 1444, 1255, 1047 cm ⁻¹ NMR(DMSO-d₆l 5) : 0.9-1.1 (6H, m), 1.09 (3H, d, J=5.5Hz), 1.4-1.6 (2H, m),1.7-2.0 (5H, m), 2.1-2.5 (3H, m), 2.5-2.6 (1H, m), 3.1-3.3 (1H, m),3.7-4.5 (16H, m), 4.7-5.1 (7H, m), 5.12 (1H, d, J=5.5Hz), 5.19 (1H, d,J=2.9Hz), 5.27 (1H, d, J=4.4Hz), 5.57 (1H, d, J=5.7Hz), 6.74 (IH, d,J=8.2Hz), 6.8-6.9 (2H, m), 7.06 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.2-7.5(3H, m), 7.97 (2H, d, J=8.9Hz), 8.0-8.2 (5H, m), 8.26 (1H, d, J=7.7Hz),8.86 (1H, s), 8.94 (1H, d, J=7.OHz) FAB-MASS : 1317 (M+Na)⁺

[0679] Analysis Calcd. for C₅₄H₆₇N₁₀O₂₂S₂Na,7H₂O:

[0680] C 45.63, H 5.74, N 9.85

[0681] Found C 45.80, H 6.05, N 9.83

Example 16

[0682] IR (KBr) : 3365, 3342, 1639, 1519, 1442, 1278, 1256, 1047 cm ⁻¹NMR (DMSO-d₆, () : (3H, d, J=6.8Hz), 1.10 (3H, d, J=6.OHz), 1.7-2.0 (3H,m), 2.1-2.4 (3H, m), 2.5-2.6 (1H, m), 3.1-3.2 (lH, m), 3.7-3.8 (2H, m),3.86 (3H, s), 3.9-4.6 (12H, m), 4.7-5.1 (7H, m), 5.09 (1H, d, J=5.6Hz),5.16 (1H, d, J=3.lHz), 5.25 (1H, d, J=4.5Hz), 5.49 (1H, d, J=5.9Hz),6.73 (1H, d, J=8.2Hz), 6.8-6.9 (2H, m), 7.06 (1H, s), 7.15 (2H, d,J=8.9Hz), 7.2-7.5 (3H, m), 7.99 (2H, d, J=8.9Hz), 8.1-8.4 (6H, m), 8.83(lH, s), 8.94 (1H, d, J=7.OHz)

[0683] FAB-MASS m/z 1275.4 (M+Na)⁺

[0684] Analysis Calcd. for C₅₁H₆₁N₁₀O₂₂S₂Na-7H₂O:

[0685] C 44.41, H 5.48, N 10.15

[0686] Found : C 44.52, H 5.35, N 10.10

Example 17

[0687] IR (KBr) : 3350, 1660, 1633, 1515, 1444, 1243, 1047 cm ⁻¹ NMR(DMSO-d₆i o) : 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.9Hz), 1.8-2.1(3H, m), 2.2-2.5 (5H, m), 2.5-2.6 (1H, m), 3.1-3.3 (1H, m), 3.7-4.6(18H, m), 4.8-5.1 (7H, m), 5.09 (1H, d, J=5.6Hz), 5.16 (1H, d, J=3.2Hz),5.24 (1H, d, J=4.5Hz), 5.54 (1H, d, J=5.9Hz), 6.73 (1H, d, J=8.2Hz),6.8-7.5 (13H, m), 7.98 (2H, d, J=8.8Hz), 8.0-8.2 (5H, m), 8.23 (1H, d,J=7.7Hz), 8.84 (1H, s), 8.91 (1H, d, J=7.lHz)

[0688] FAB-MASS : m/z =1395 (M+Na)⁺

[0689] Analysis Calcd. for C₅₉H₆₉N₁₀O₂₃NaS₂-5H₂O:

[0690] C 48.42, H 5.44, N 9.57

[0691] Found : C 48.28, H 5.42, N 9.52

Example 18

[0692] IR (KBr) 3350, 1668, 1631, 1537, 1513, 1442, 1278, 1245, 1043 cm⁻¹ NMR (DMSO-d₆, 6) : 0.87 (3H, t, J=6.8Hz), 0.96 (3H, d, J=6.8Hz), 1.08(3H, d, J=5.9Hz), 1.2-1.4 (10H, m), 1.4-1.6 (2H, m), 1.7-2.0 (5H, m),2.1-2.6 (8H, m), 3.0-3.3 (5H, m), 3.7-4.5 (16H, m), 4.7-5.1 (7H, m),5.08 (lH, d, J=5.6Hz), 5.14 (1H, d, J=3.2Hz), 5.22 (1H, d, J=4.6Hz),5.51 (1H, d, J=6.0Hz), 6.73 (lH, d, J=8.2Hz), 6.8-7.0 (2H, m), 7.0-7.4(4H, m), 8.0- 8.2 (5H, m), 8.20 (1H, d, J=7.7Hz), 8.83 (1H, s), 8.92(1H, d, J=7.OHz)

[0693] FAB-MASS : m/z =1364.2 (M+2Na)⁺

[0694] Analysis Calcd. for C₅₇H₈₁N₁₁l₂₁S₂6H₂O:

[0695] C 47.92, H 6.56, N 10.79

[0696] Found : C 48.19, H 6.38, N 10.65

Example 19

[0697] IR (KBr) : 3325, 1675, 1648, 1540, 1513 cm⁻¹ NMR (DMSO-d₆₁ o)0.87 (3H, t, J=7.2Hz), 0.96 (3H, d, J=6.7Hz), 1.08 (3H, d, J=5.7Hz),1.2-1.5 (6H, m), 1.6-2.0 (5H, m), 2.1-2.4 (3H, m), 2.5-2.6 (lH, in),3.03 (2H, t, J=7.9Hz), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.6-3.8 (2H,m), 3.8-4.5 (14H, m), 4.7-5.2 (7H, m), 5.09 (1H, d, J=5.6Hz), 5.16 (1H,d, J=3.lHz), 5.25 (1H, d, J=4.5Hz), 5.49 (1H, d, J=5.9Hz), 6.73 (1H, d,J=8.2Hz), 6.8-7.0 (4H, m), 7.05 (1H, s), 7.2-7.5 (5H, m), 8.0-8.2 (5H,m), 8.22 (1H, d, J=7.7Hz), 8.84 (1H, s), 8.91 (1H, d, J=7.OHz)

[0698] APCI-MASS : m/z =1373.5 (M+Na)⁺

[0699] Analysis Calcd. for C₅₈H₇₅N₁₀O₂₂S₂Na-6H₂O:

[0700] C 47.73, H 6.01, N 9.60

[0701] Found : C 47.89, H 6.21, N 9.47

Example 20

[0702] IR (KBr) 3334, 2944, 1668, 1631, 1533, 1452, 1278, 1249, 1079 cm⁻¹ NMR (DMSO-d₆, o) : 0.90 (3H, t, J=7.0Hz), 0.96 (3H, d, J=6.7Hz), 1.08(3H, d, J=5.7Hz), 1.3-1.5 (4H, m), 1.7-2.1 (5H, m), 2.1-2.4 (3H, m),2.6-2.7 (1H, m), 3.1-3.3 (1H, m), 3.6-4.5 (16H, m), 4.7-5.1 (7H, m), 105.11 (1H, d, J=5.5Hz), 5.18 (1H, d, J=3.OHz), 5.26 (1H, d, J=4.4Hz),5.54 (1H, d, J=5.8Hz), 6.73 (1H, d, J=8.2Hz), 6.8-7.1 (5H, m), 7.2-7.4(3H, m), 7.45 (1H, d, J=3.8Hz), 7.6-7.8 (3H, m), 7.76 (2H, d, J=8.3Hz),7.95 (2H, d, J=8.3Hz), 8.10 (1H, d, 1ri-5 J=8.2Hz), 8.26 (1H, d,J=7.7Hz), 8.75 (1H, d, J=7.OHz), 8.85 (1H, s)

[0703] FAB-MASS : m/z =1329.3 (M+Na)⁺

[0704] Analysis Calcd. for C57H7lN8O22S2Na6.5H₂ O:

[0705] C 48.06, H 5.94, N 7.87

[0706] Found : C 48.14, H 6.21, N 7.82

Example 21

[0707] IR (KBr) 3376, 2925, 1668, 1631, 1504, 1247 cm ⁻¹ NMR (DMSO-d₆,o) 0.90 (3H, t, J=7.2Hz), 0.96 (3H, d, J=6.7Hz), 1.08 (3H, d, J=5.4Hz),1.3-1.5 (4H, m), 1.6-2.1 (5H, m), 2.2-2.6 (4H, m), 3.1-3.3 (lH, m),3.6-4.6 (16H, m), 4.7-5.2 (7H, m), 5.11 (lH, d, J=5.5Hz), 5.16 (lH, d,J=3.lHz), 5.26 (lH, d, J=4.4Hz), 5.54 (lH, d, J=5.9Hz), 6.73 (lH, d,J=8.2Hz), 6.8-7.5 (1OH, m), 7.77 (2H, d, J=8.7Hz), 7.86 (2H, d,J=8.4Hz), 7.97 (2H, d, J=8.4Hz), 8.08 (1H, d, J=8.2Hz), 8.25 (1H, d,J=7.7Hz), 8.75 (1H, d, J=7.OHz), 8.85 (lH, s)

[0708] FAB-MASS : m/z =1313.9 (M+Na)⁺

[0709] Analysis Calcd. for C₅₇H₇₁N₈0₂₃SNa-7H₂O:

[0710] C 48.30, H 6.04, N 7.91

[0711] Found : C 48.56, H 6.30, N 7.90

Example 22

[0712] To a solution of 1-hydroxybenzotriazole (45.5 mg) and4-[4-(4-cyclohexylphenyl)piperazin-1-yl]methylbenzoic acid hydrochloride(106 mg) in the mixture of triethylamine (78.1 μl) and dimethylformamide(2.6 ml) was added 1-ethyl-3-(3′- dimethylaminopropyl)carbodiimidehydrochloride (80.3 mg) and stirred for 2 hours at ambient temperature.Then to the reaction mixture was added The Starting Compound (262.4 mg)and 4-dimethylaminopyridine (37.7 mg) and stirred for 4 hours at ambienttemperature. The reaction mixture was pulverized with ethyl acetate. Theprecipitate was collected by filtration and dried over reduced pressure.The powder was added to water and subjected to ion-exchange columnchromatography on DOWEX-50WX4 and eluted with water. The fractionscontaining The Object Compound were combined and subjected to columnchromatography on ODS (YMC-gel ODS-AM S-50) and eluted with 30-50%acetonitrile aq. The fractions containing The Object Compound werecombined and evaporated under reduced pressure to remove acetonitrile.The residue was lyophilized to give The Object Compound (22) (55 mg).

[0713] IR (KBr) 3363.2, 1666.2, 1631.5, 1274.7 cm ⁻¹ NMR (DMSO-d₆, 5) :0.96 (3H, d, J=6.6Hz), 1.07 (3H, d, J=5.8Hz), 0.9-2.1 (13H, m), 2.1-2.7(SH, m), 3.1- 3.6 (9H, m), 3.6-4.6 (16H, m), 4.7-5.6 (11H, m), 6.73 (1H,d, J=8.2Hz), 6.8-6.95 (4H, m), 7.06 (lH, s), 7.09 (2H, d, J=8.4Hz),7.2-7.5 (3H, m), 7.6 (2H, d, J=7.3Hz), 8.1 (1H, d, J=8.7Hz), 8.3 (1H, d,J=8.7Hz), 8.78 (1H, d, J=6.7Hz), 8.84 (lH, s)

[0714] FAB-MASS m/z =1240 (M-SO₃+Na)⁺

[0715] The Object Compounds (23) to (30) were obtained according to asimilar manner to that of Example 22.

Example 23

[0716] IR (KBr) 3350, 2929, 1673, 1646, 1631, 1538, 1513, 1456, 1247,1047 cm ⁻¹ NMR (DMSO-d₆, 5) : 0.90 (3H, t, J=7.2Hz), 0.96 (3H, d,J=6.9Hz), 1.08 (3H, d, J=5.7Hz), 1.2-1.5 (4H, m), 1.7-2.0 (5H, m),2.1-2.5 (3H, m), 2.6-2.7 (1H, m), 3.7-4.6 (16H, m), 4.8-5.1 (7H, m),5.09 (1H, d, J=5.SHz), 5.16 (1H, d, J=3.lHz), 5.24 (1H, d, J=4.5Hz),5.52 (1H, d, J=5.7Hz), 6.73 (1H, d, J=8.3Hz), 6.8-7.0 (2H, m), 7.0-7.1(3H, m), 7.2-7.5 (3H, m), 7.51 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.2Hz),7.93 (2H, d, J=8.2Hz), 8.10 (1H, d, J=8.4Hz), 8.24 (1H, d, J=:7.7Hz),8.81 (1H, d, J=7.OHz), 8.84 (1H, s)

[0717] FAB-MASS m/z =1271 (M+Na)⁺

[0718] Analysis Calcd. for C₅₅H₆₉N₈ ₂₂SNa-6H₂

[0719] C 48.67, H 6.02, N 8.26

[0720] Found : C 48.82, H 6.18, N 8.20

Example 24

[0721] IR (KBr) : 3365, 2935, 2873, 1656, 1631, 1535, 1457, 1247, 1047cm ⁻¹ NMR (DMSO-d₆, 5) 0.87 (3H, t, J=7.2Hz), 0.96 (3H, d, J=6.7Hz),1.12 (3H, d, J=5.7Hz), 1.3-1.5 (4H, m), 25 1.6-2.1 (SH, m), 2.2-2.5 (4H,m), 3.1-3.3 (1H, m), 3.6-3.8 (2H, m), 4.0-4.6 (14H, m), 4.8-5.0 (3H, m),5.0-5.2 (6H, m), 5.24 (1H, d, J=4.5Hz), 5.56 (1H, d, J=5.7Hz), 6.73 (1H,d, J=8.2Hz), 6.8-6.9 (2H, m), 7.0-7.5 (6H, ma), 7.70 (2H, d, J=8.8Hz),7.79 (2H, d, J=8.5Hz), 8.0-8.1 (2H, m), 8.13 (2H, d, J=8.SHz), 8.30 (1H,s), 8.62 (1H, d, J=7.OHz), 8.83 (1H, s)

[0722] FAB-MASS : m/z =1330 (M+Na)⁺

[0723] Analysis Calcd. for C₅₆H₇₀N₉O₂₂S₂Na,6H₂O:

[0724] C 47.49, H 5.84, N 8.90

[0725] Found : C 47.87, H 5.49, N 8.88

Example 25

[0726] IR (KBr) : 3359, 1673.9, 1648.8, 1257.4 cm ⁻¹ NMR (DMSO-d₆, 5) :0.91 (3H, t, J=7.lHz), 0.96 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.9Hz),1.3-1.5 (4H, m), 1.6-2.7 (9H, m), 3.19 (1H, m), 3.6-4.6 (15H, m),4.7-5.3 (11H, m), 5.53 (1H, d, J=5.9Hz), 6.73 (1H, d, J=8.3Hz), 6.83(1H, d, J=8.3Hz), 6.88 (1H, s), 7.06 (1H, s), 7.14 (2H, d, J=8.9Hz),7.2-7.4 (3H, m), 7.90 (2H, d, J=8.9Hz), 7.97 (4H, m), 8.08 (lH, d,J=6Hz), 8.31 (1H, d, J=5Hz), 8.76 (lH, d, J=5Hz), 8.85 (lH, s), 8.86(1H, s)

[0727] FAB-MASS m/z =1325 (M+Na)⁺

[0728] Analysis Calcd. for C₅₇H₇₀N₁₁O₂₂S₂N&L8H₂O:

[0729] C 45.87, H 5.81, N 10.32

[0730] Found C 46.04, H 5.77, N 10.28

Example 26

[0731] IR (KBr) 3334, 1668.1, 1648.8, 1631.5 cm ⁻¹ NMR (DMSO-d₆, 5) 0.97(3H, d, J=6.6Hz), 1.08 (3H, d, J=5.lHz), 1.36 (3H, t, J=6.9Hz), 1.6-2.7(7H, m), 3.17 (1H, m), 3.6-4.6 (15H, m), 4.7-5.3 (11H, m), 5.53 (1H, d,J=5.8Hz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.87 (1H, s),7.04 (1H, s), 7.06 (2H, d, J=8.7Hz), 7.2-7.5 (3H, m), 7.73 (2H, d,J=8.7Hz), 7.87 (2H, d, J=8.4Hz), 7.8-8.2 (7H, m), 8.26 (1H, d, J=7.9Hz),8.75 (1H, d, J=7Hz), 8.85 (1H, s), 8.92 (1H, s)

[0732] FAB-MASS : m/z =1358 (M+Na)⁺

Example 27

[0733] IR (KBr) : 3355.5, 1666.2, 1631.5 cm ⁻¹ NMR (DMSO-d₆₁ 5) : 0.97(3H, d, J=6.7Hz), 1.09 (3H, d, J=5.6Hz), 1.7-2.7 (7H, m), 3.18 (1H, m),3.6-4.6 (13H, m), 4.7-5.3 (11H, m), 5.53 (1H, d, J=5.9Hz), 6.73 (1H, d,J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.86 (1H, s), 7.05 (lH, s), 7.2-7.6(6H, m), 7.79 (2H, d, J=6.9Hz), 7.9-8.2 (9H, m), 8.27 (1H, d, J=7.9Hz),8.76 (1H, d, J=7Hz), 8.85 (1H, s), 8.93 (1H, s)

[0734] FAB-MASS : m/z =1314 (M-Na)⁺

Example 28

[0735] IR (KBr) : 3357.5, 1648.8, 1631.5, 1261.2 cm ⁻¹ NMR (DMSO-d₆, o): 0.91 (3H, t, J=7.lHz), 0.96 (3H, d, J=8.lHz), 1.09 (3H, d, J=7.5Hz),1.3-1.5 (4H, m), 1.6-2.7 (9H, m), 3.19 (1H, m), 3.6-4.6 (15H, m),4.7-5.3 (1lH, m), 5.53 (1H, d, J=5.8Hz), 6.73 (1H, d, J=8.3Hz), 6.82(1H, d, J=8.3Hz), 6.85 (1H, s), 7.05 (1H, s), 7.19 (2H, d, J=9.OHz),7.1-7.5 (3H, m), 7.9-8.2 (7H, m), 8.28 (1H, d, J=8.3Hz), 8.85 (1H, s),8.92 (1H, d, J=7.2Hz)

[0736] FAB-MASS : m/z =1302 (M-Na)⁺

[0737] Analysis Calcd. for C₅₆H₆₉ClN₉O₂₃SNa-7H₂O:

[0738] C 46.30, H 5.76, N 8.60

[0739] Found : C 46.57, H 5.67, N 8.69

Example 29

[0740] IR (KBr) 3344.0, 1664.3, 1627.6 cm ⁻¹ NMR (DMSO-d₆l 5) : 0.86(3H, t, J=6.5Hz), 0.96 (3H, d, J=6.SHz), 1.04 (3H, d, J=5.6Hz), 0.8-1.6(14H, m), 1.7-2.6 (11H, m), 3.0-3.6 (9H, m), 3.6-4.5 (13H, rm), 4.6-5.3(11H, m), 5.45 (1H, d, J=6.OHz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d,J=8.2Hz), 6.84 (lH, s), 7.02 (2H, d, J=8.6Hz), 7.05 (1H, s), 7.2-7.5(3H, m), 7.83 (2H, d, J=8.6Hz), 8.08 (1H, d, J=8.8Hz), 8.28 (1H, d,J=7.4Hz), 8.47 (1H, d, J=6.4Hz), 8.84 (1H, s)

[0741] FAB-MASS : m/z =1275 (M+Na)⁺

[0742] Analysis Calcd: for C₅₇H₈₄N₁₀O₂₁S-9H₂O:

[0743] C 47.56, H 7.14, N 9.73

[0744] Found C 47.73, H 6.93, N 9.68

Example 30

[0745] IR (KBr) 3361.3, 1668.1, 1631.5 cm ⁻¹ NMR (DMSO-d₆l 5) : 0.96(3H, d, J=6.7Hz), 1.06 (3H, d, J=5.8Hz), 1.1-1.5 (6H, m), 1.5-2.1 (7H,m), 2.1-3.5 (18H, m), 3.5-4.5 (13H, m), 4.7-5.3 (11H, m), 5.50 (1H, d,J=5.9Hz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.84 (1H, s),6.85 (1H, d, J=8.lHz), 7.04 (1H, s), 7.06 (1H, d, J=8.lHz), 7.2-7.5 (5H,m), 7.83 (2H, d, J=8.lHz), 8.08 (1H, d, J=9.7Hz), 8.28 (1H, d, J=8Hz),8.66 (1H, d, J=7.2Hz), 8.85 (1H, s)

[0746] FAB-MASS m/z 1309 (M+Na)⁺

[0747] Analysis Calcd. for C₆₀H₈₂N₁₀ ₂₁S6H₂O

[0748] C 50.77, H 6.67, N 9.87

[0749] Found : C 50.78, H 6.82, N 9.70

[0750] The Starting Compound (31) in the following Example 31 and TheObject Compound (31) in the following Example 31 are illustrated bychemical formulae as below.

[0751] The Starting Compound (31)

[0752] The Object Compound (31)

Example 31

[0753] To a solution of Starting Compound (31) (5.2 g) in the mixture oftetrahydrofuran (105 ml), N,N-dimethylformamide (21 ml) andchlorotrimethylsilane (20.4 ml) was added triethylamine (33.6 ml) underice-cooling and stirred for 12 hours at ambient temperature. Theinsoluble material was filtered off and the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using n-hexane/ethyl acetate (4:1) aseluent. The fractions containing the object compound were combined andevaporated under reduced pressure. To the residue was added the mixtureof acetic acid (10 ml) and methanol (30 ml) and stirred for 1 hour atambient temperature. The reaction mixture was pulverized withdiisopropyl ether. The precipitate was collected by filtration and driedover reduced pressure. The powder was added to 60% methanol in water andsubjected to column chromatography on ODS (YMC-gel ODS-AM S-50) andeluted with 30% acetonitrile in water. The fractions containing theobject compound were combined and evaporated under reduced pressure toremove acetonitrile. The residue was lyophilized to give Object Compound(31) (1.5 g).

[0754] IR (KBr) : 3353.6, 1658.5, 1633.4, 1456.0 cm ¹

[0755] FAB-MASS : m/z =1211 (M+Na)⁺

[0756] The Starting Compound (32) in the following Example 32 and theObject Compound (32) in the following Example 32 are illustrated bychemical formulae as below.

[0757] The Starting Compound (32)

[0758] The Object Compound (32)

Example 32

[0759] To a solution of Starting Compound (32) (10 g) in the mixture oftetrahydrofuran (200 ml), N,N-dimethylformamide (50 ml) andchlorotrimethylsilane (36.3 ml) was added triethylamine (59.8 ml) underice-cooling and stirred for 12 hours at ambient temperature. Theinsoluble material was filtered off and the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using n-hexane/ethyl acetate (4:1) aseluent. The fractions containing the object compound were combined andevaporated under reduced pressure. To a solution of the residue in themixture of methanol (15 ml) and acetonitrile (15 ml) was addedtrimethylsilyldiazomethane (2M solution in hexane, 0.98 ml) anddiisopropylethylamine (0.343 ml) and stirred for 4 hours at ambienttemperature. The reaction mixture was added to saturated sodiumbicarbonate aqueous solution and extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate. Magnesium sulfate wasfiltered off, and the filtrate was evaporated under reduced pressure. Toa solution of the residue in tetrahydrofuran (30 ml) was added themixture of acetic acid (3.76 ml) and tetra-n-butylammonium fluoride (lMsolution in tetrahydrofuran, 65.6 ml) and stirred for 2 hours under ice-cooling. The reaction mixture was pulverized with water. The precipitatewas collected by filtration and dried over reduced pressure. The powderwas purified by column chromatography on silica gel usingdichloromethane/acetic acid/methanol/water (4:1:1:1) as eluent. Thefractions containing the object compound were combined and evaporatedunder reduced pressure to give Object Compound (32) (280 mg).

[0760] NMR (DMSO-d₆l 6) : 0.91 (3H, t, J=7.OHz), 0.96 (3H, d, J=6.5Hz),1.09 (3H, d, J=5.7Hz), 1.3-1.5 (4H, m), 1.6-2.7 (9H, m), 3.16 (lH, m),3.75 (3H, s), 3.9- 4.6 (15H, m), 4.7-5.3 (11H, m), 5.54 (IH, d,J=5.8Hz), 6.6-6.8 (3H, m), 6.87 (lH, s), 7.12 (2H, d, J=8.9Hz), 7.2-7.5(3H, m), 7.55 (lH, s), 7.85 (2H, d, J=8.9Hz), 7.9-8.1 (5H, m), 8.29 (lH,d, J=7.7Hz), 8.86 (lH, s), 8.85 (lH, s), 8.71 (lH, d, J=7Hz)

[0761] FAB-MASS : m/z =1226 (M+Na)⁺

1. A polypeptide compound of the following general formula [I]:

wherein R¹ is aroyl substituted with heterocyclic group which has asuitable substituent selected from the group consisting of aryl havingcyclo(lower)alkyloxy, aryl having morpholinyl, aryl havingaryloxy(lower)alkoxy, heterocyclic group having cyclo(lower)alkyl,heterocyclic group having higher alkyl, ar(lower)alkyl having loweralkoxy, and cyclo(lower)alkyl which may have one or more suitablesubstituent s); aroyl substituted with heterocyclic group which hashydroxy and may have additional one or more suitable substituent(s);aroyl substituted with piperidyl which has aryl having lower alkoxy;aroyl substituted with thiadiazolyl which has a suitable substituentselected from the group consisting of aryl having pentyl, aryl havinghexyl, aryl having methoxy, aryl having butoxy, and aryl having higheralkoxy; aroyl substituted with aryl which has aryl having pentyloxy;aroyl substituted with piperazinyl which has 3-hexyloxyphenyl; aroylsubstituted with 1,2,3,6-tetrahydropyridyl which may have one or moresuitable substituent(s); aroyl substituted with thienyl which may haveone or more suitable substituent(s); aroyl substituted with furyl whichmay have one or more suitable substituent(s); aroyl substituted withheterocyclic(lower)alkyl which may have one or more suitablesubstituent(s); aroyl substituted with ar(lower)alkynyl which may haveone or more suitable substituent(s); lower alkanoyl substituted withthiazolyl which may have one or more suitable substituent(s); aroylsubstituted with imidazothiazolyl which may have one or more suitablesubstituent(s); aroyl substituted with isoxazolyl having halogen whichmay have one or more suitable substituent(s); or4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl; and R2 is hydroxy,hydroxysulfonyloxy or lower alkoxy, with proviso that R² is nothydroxysulfonyloxy, when R¹ is4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl, and a salt thereof.
 2. Acompound of claim 1, wherein R¹ is benzoyl substituted with piperazinylwhich has cyclo(lower)alkyl having cyclo(lower)alkyl, benzoylsubstituted with piperazinyl which has phenyl havingcyclo(lower)alkyloxy, benzoyl substituted with piperazinyl which hasphenyl having morpholinyl, or benzoyl substituted with piperazinyl whichhas phenyl having 3-hexyloxy.
 3. A compound of claim 1, wherein R¹ isbenzoyl substituted with piperidyl which has hydroxy and phenyl havinglower alkoxy, benzoyl substituted with piperidyl which has phenyl havinglower alkoxy, or benzoyl substituted with piperidyl which has piperidylhaving cyclo(lower)alkyl.
 4. A compound of claim 1, wherein R¹ isbenzoyl substituted with 1,2,3,6-tetrahydropyridyl which has phenylhaving lower alkoxy.
 5. A compound of claim 1, wherein R¹ is benzoylsubstituted with phenyl which has phenyl having pentyloxy.
 6. A compoundof claim 1, wherein R¹ is benzoyl substituted with thiadiazolyl whichhas phenyl having methoxy, benzoyl substituted with thiadiazolyl whichhas phenyl having butoxy, benzoyl substituted with thiadiazolyl whichhas phenyl having pentyl, benzoyl, substituted with thiadiazolyl whichhas phenyl having hexyl, benzoyl substituted with thiadiazolyl which hasphenyl having higher alkoxy, benzoyl substituted with thiadiazolyl whichhas phenyl having phenoxy(lower)alkoxy, benzoyl substituted withthiadiazolyl which has piperidyl having higher alkyl, and benzoylsubstituted with thiadiazolyl which has phenyl(lower)alkyl having loweralkoxy.
 7. A compound of claim 1, wherein R¹ is benzoyl substituted withthienyl which has phenyl having lower alkoxy, or benzoyl substitutedwith furyl which has phenyl having lower alkoxy.
 8. A compound of claim1, wherein R¹ is benzoyl substituted with piperazinyl(lower)alkyl whichhas phenyl having cyclo(lower)alkyl, or benzoyl substituted withphenyl(lower)alkynyl which has lower alkoxy.
 9. A compound of claim 1,wherein R¹ is thiazolyl-carbonyl substituted with phenyl which hasphenyl having lower alkoxy.
 10. A process for the preparing apolypeptide compound [I] of claim 1, which comprises 1) reacting acompound of the formula

or its reactive derivative at the amino group or a salt thereof, with acompound of the formula R ¹ - OH   [III] wherein R¹ and R² are definedin claim 1, or its reactive derivative at the carboxy group or a saltthereof, to give a compound [I] or the formula

wherein R¹ and R² are defined in claim 1, or a salt thereof, or 2)subjecting a compound [Ia] of the formula

wherein R¹ is defined in claim 1, R_(a) ² is hydroxysulfonyloxy or asalt thereof, to hydrolysis reaction of the sulfonic acid group, to givea compound [Ib] of the formula

wherein R¹ is defined in claim 1, R_(b) ² is hydroxy or a salt thereof,or 3) subjecting a compound [Ib] of the formula

wherein R¹ is defined in claim 1, R_(b) ² is hydroxy or its reactivederivative at the hydroxy group or a salt thereof, to alkylationreaction of the hydroxy group, to give a compound [Ic] of the formula11. A pharmaceutical composition which comprises, as an activeingredient, a compound of claim 1 or a pharmaceutically acceptable saltthereof in admixture with pharmaceutically acceptable carriers orexcipients.
 12. Use of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof as a medicament.
 13. A compound of claim 1 or apharmaceutically acceptable salt thereof for use as a medicament.
 14. Amethod for the prophylactic and/or the therapeutic treatment ofinfectious diseases caused by pathogenic microormanisms which comprisesadministering a compound of claim 1 or a pharmaceutically acceptablesalt thereof to a human being or an animal.

wherein R¹ is defined in claim 1, R_(c) ²is lower alkoxy or a saltthereof.